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Wang Y, Li GW, Zhu SL, Xu TT, Qin YW, Cheng CQ, Zheng QW, He C, Zhou BD, Fang SQ. NMDAR2B/PKA/CREB signaling pathway contributes to esophageal neuropathic pain in gastroesophageal reflux disease. World J Gastroenterol 2025; 31:98974. [PMID: 40124269 PMCID: PMC11924000 DOI: 10.3748/wjg.v31.i11.98974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 12/10/2024] [Accepted: 02/17/2025] [Indexed: 03/13/2025] Open
Abstract
BACKGROUND Esophageal hypersensitivity is an important cause of refractory gastroesophageal reflux disease, in which patients do not respond to standard acid-suppressive therapy and suffer from continuous noncardiac chest pain and regurgitation. The N-methyl-D-aspartate receptor (NMDAR) may play a crucial role in the development of visceral hypersensitivity in functional gastrointestinal disorders. However, the specific mechanisms of visceral hypersensitivity in upper digestive tract diseases remain poorly understood. AIM To investigate the role of the NMDAR2B/protein kinase A (PKA)/cAMP-response element binding protein (CREB) signaling pathway in the development of esophageal neuropathic pain associated with gastroesophageal reflux disease (GERD). METHODS Thirty-six 6-week-old specific pathogen free rats were randomly assigned to six groups: the control, model, model + NMDAR agonist, model + NMDAR antagonist, model + PKA antagonist, and model + NMDAR antagonist + PKA agonist groups, with six rats in each group. The model was induced via an intraperitoneal injection of ovalbumin for sensitization along with local esophageal stimulation. Immunohistochemistry and Western blotting were utilized to assess the expression levels of NMDAR2B signaling pathway-related proteins in the cingulate gyrus, dorsal thalamus, spinal dorsal horn, and peripheral esophageal tissues. RT-PCR was used to measure the corresponding mRNA expression, and ELISA was used to determine the serum brain-derived neurotrophic factor (BDNF) concentration. Behavioral scoring was performed during balloon distention and acid perfusion of the lower esophagus. RESULTS Compared with the control group, the model group presented significantly increased expression levels of the NMDAR2B, PKA, CREB, BDNF, substance P, and calcitonin gene-related peptide proteins and mRNAs in the cingulate gyrus, dorsal thalamus, spinal dorsal horn, and lower esophagus (P < 0.05). Compared with the model group, the model + NMDAR agonist group exhibited even higher expression levels of these proteins and mRNAs (P < 0.05), whereas the model + NMDAR antagonist and model + PKA antagonist groups presented lower expression levels (P < 0.05). The model + NMDAR antagonist + PKA agonist group presented higher expression levels than did the model + NMDAR antagonist group (P < 0.05). The changes in the serum BDNF concentration and behavioral score during balloon distention and acid perfusion were consistent with these changes in expression. CONCLUSION The NMDAR2B signaling pathway plays a critical role in the development of neuropathic pain in GERD through the PKA/CREB/BDNF pathway.
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Affiliation(s)
- Yi Wang
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Guan-Wu Li
- Department of Radiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Sheng-Liang Zhu
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Ting-Ting Xu
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Yi-Wen Qin
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Chuan-Qi Cheng
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Qin-Wei Zheng
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Cong He
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Bing-Duo Zhou
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Sheng-Quan Fang
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
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2
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Kim JY, Kim H, Chung WS, Park H. Selective regulation of corticostriatal synapses by astrocytic phagocytosis. Nat Commun 2025; 16:2504. [PMID: 40082427 PMCID: PMC11906744 DOI: 10.1038/s41467-025-57577-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 02/25/2025] [Indexed: 03/16/2025] Open
Abstract
In the adult brain, neural circuit homeostasis depends on the constant turnover of synapses via astrocytic phagocytosis mechanisms. However, it remains unclear whether this process occurs in a circuit-specific manner. Here, we reveal that astrocytes target and eliminate specific type of excitatory synapses in the striatum. Using model mice lacking astrocytic phagocytosis receptors in the dorsal striatum, we found that astrocytes constantly remove corticostriatal synapses rather than thalamostriatal synapses. This preferential elimination suggests that astrocytes play a selective role in modulating corticostriatal plasticity and functions via phagocytosis mechanisms. Supporting this notion, corticostriatal long-term potentiation and the early phase of motor skill learning are dependent on astrocytic phagocytic receptors. Together, our findings demonstrate that astrocytes contribute to the connectivity and plasticity of the striatal circuit by preferentially engulfing a specific subset of excitatory synapses within brain regions innervated by multiple excitatory sources.
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Affiliation(s)
- Ji-Young Kim
- Research group for Neurovascular Unit, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea
| | - Hyeyeon Kim
- Research group for Neurovascular Unit, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea
- Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea
| | - Won-Suk Chung
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Hyungju Park
- Research group for Neurovascular Unit, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea.
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3
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Huang F, Baset A, Bello ST, Chen X, He J. Cholecystokinin facilitates the formation of long-term heterosynaptic plasticity in the distal subiculum. Commun Biol 2025; 8:153. [PMID: 39893259 PMCID: PMC11787286 DOI: 10.1038/s42003-025-07597-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 01/22/2025] [Indexed: 02/04/2025] Open
Abstract
It has been well established that Cornu Ammonis-(CA1) and subiculum (SUB) serve as the major output components of the entorhinal-hippocampal circuitry. Nevertheless, how the neuromodulators regulate the neurocircuitry in hippocampal formation has remained elusive. Cholecystokinin (CCK), is the most abundant neuropeptide in the central nervous system, which broadly regulates the animal's physiological status at multiple levels, including neuroplasticity and its behavioral consequences. Here, we uncover that exogenous CCK potentiates the excitatory synaptic transmission in the CA1-SUB projections via CCK-B receptor. Dual-color light theta burst stimulation elicits heterosynaptic long-term potentiation in distal SUB region. Light activation of medial entorhinal cortex (MEC) derived CCK-positive neurons triggers the CCK release in the SUB. Neuronal activities of SUB-projecting MECCCK neurons are necessary for conveying and processing of navigation-related information. In conclusion, our findings prove a crucial role of CCK in regulating neurobiological functions in the SUB region.
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Affiliation(s)
- Fengwen Huang
- Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong, China.
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, China.
| | - Abdul Baset
- Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong, China
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, China
| | - Stephen Temitayo Bello
- Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong, China
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, China
| | - Xi Chen
- Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong, China
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong, China
| | - Jufang He
- Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong, China.
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong, China.
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4
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Han J, Park H. Recycling of endocytic BDNF through extracellular vesicles in astrocytes. Sci Rep 2025; 15:2011. [PMID: 39814913 PMCID: PMC11735857 DOI: 10.1038/s41598-025-86200-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 01/08/2025] [Indexed: 01/18/2025] Open
Abstract
Brain-derived neurotrophic factor (BDNF) plays an essential role in regulating diverse neuronal functions in an activity-dependent manner. Although BDNF is synthesized primarily in neurons, astrocytes can also supply BDNF through various routes, including the recycling of neuron-derived BDNF. Despite accumulating evidence for astrocytic BDNF uptake and resecretion of neuronal BDNF, the detailed mechanisms underlying astrocytic BDNF recycling remain unclear. Here, we report that astrocytic resecretion of endocytosed BDNF is mediated by an extracellular vesicle (EV)-dependent secretory pathway. In cultured primary astrocytes, extracellular BDNF was endocytosed into CD63-positive EVs, and stimulation of astrocytes with ATP could evoke the release of endocytosed BDNF from CD63-positive vesicles. Downregulation of vesicle-associated membrane protein 3 (Vamp3) led to an increase in the colocalization of endosomal BDNF and CD63 but a decrease in extracellular vesicle release, suggesting the necessity of Vamp3-dependent signaling for EV-mediated BDNF secretion. Collectively, our findings demonstrate that astrocytic recycling of neuronal BDNF is dependent on the EV-mediated secretory pathway via Vamp3-associated signaling.
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Affiliation(s)
- Jeongho Han
- Neurovascular Unit Research Group, Korea Brain Research Institute (KBRI), Daegu, South Korea
| | - Hyungju Park
- Neurovascular Unit Research Group, Korea Brain Research Institute (KBRI), Daegu, South Korea.
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5
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Antonijevic M, Dallemagne P, Rochais C. Indirect influence on the BDNF/TrkB receptor signaling pathway via GPCRs, an emerging strategy in the treatment of neurodegenerative disorders. Med Res Rev 2025; 45:274-310. [PMID: 39180386 DOI: 10.1002/med.22075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/06/2022] [Accepted: 08/04/2024] [Indexed: 08/26/2024]
Abstract
Neuronal survival depends on neurotrophins and their receptors. There are two types of neurotrophin receptors: a nonenzymatic, trans-membrane protein of the tumor necrosis factor receptor (TNFR) family-p75 receptor and the tyrosine kinase receptors (TrkR) A, B, and C. Activation of the TrkBR by brain-derived neurotrophic factor (BDNF) or neurotrophin 4/5 (NT-4/5) promotes neuronal survival, differentiation, and synaptic function. It is shown that in the pathogenesis of several neurodegenerative conditions (Alzheimer's disease, Parkinson's disease, Huntington's disease) the BDNF/TrkBR signaling pathway is impaired. Since it is known that GPCRs and TrkR are regulating several cell functions by interacting with each other and generating a cross-communication in this review we have focused on the interaction between different GPCRs and their ligands on BDNF/TrkBR signaling pathway.
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6
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Wong YT, Zheng X, Lau SH, Sun KHM, Chen X, Li H, Ng SL, Jiang H, Lau GCY, He J. Artificial fluorescent sensor reveals pre-synaptic NMDA receptors switch cholecystokinin release and LTP in the hippocampus. J Neurochem 2024; 168:2621-2639. [PMID: 38750623 DOI: 10.1111/jnc.16128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 04/23/2024] [Accepted: 04/29/2024] [Indexed: 10/04/2024]
Abstract
Cholecystokinin (CCK) has been confirmed to be essential in NMDA-dependent long-term potentiation (LTP) at mouse cortical synapses. This paper has proven that CCK is necessary for LTP induced by high-frequency stimulation of mouse hippocampal synapses projected from the entorhinal cortex. We show that the subunit of the axonal NMDA receptor dominant modulates the activity-induced LTP by triggering pre-synaptic CCK release. A functional pre-synaptic NMDA receptor is required to induce LTP mediated by the axonal Ca2+ elevation and CCK exocytosis at CCK-specific neurons. Genetic depletion of the GluN1 subunit of NMDA receptors on CCK neurons, which projected from the entorhinal cortex largely abolished the axonal Ca2+ elevation and disturbed the secretion of CCK in hippocampus. These results demonstrate that activity-induced LTP at the hippocampal synapse is CCK-dependent, and CCK secretion from the axonal terminal is modulated by pre-synaptic NMDA receptors.
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Grants
- CityU11101521, CityU11103922, CityU11104923 Hong Kong Research Grants Council, General Research Fund
- Ref The College Research Grant under Hong Kong Tung Wah College
- 2023-00-51CRG230204 The College Research Grant under Hong Kong Tung Wah College
- C1043-21G Hong Kong Research Grants Council, Collaborative Research Fund
- T13-605/18-W Hong Kong Research Grants Council, Theme-Based Research Scheme
- SRFS2324-1S02 Hong Kong Research Grants Council, Senior Research Fellow Scheme
- GHP_075_19GD Innovation and Technology Fund of the Hong Kong SAR, China
- 09203656, 08194106 Hong Kong Health Bureau, Health and Medical Research Fund
- Health@InnoHKprogram Innovation Technology Commission of the Hong Kong SAR, China
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Affiliation(s)
- Yin-Ting Wong
- Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong
- School of Medical and Health Sciences, Tung Wah College, Ho Man Tin, Hong Kong
| | - Xuejiao Zheng
- Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong
- City University of Hong Kong Shenzhen Research Institute, Shenzhen, China
| | - Siu-Hin Lau
- Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong
| | - Ka-Hei Murphy Sun
- Department of Pathology, Princess Margaret Hospital, Hong Kong City, Hong Kong
| | - Xi Chen
- Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong
- City University of Hong Kong Shenzhen Research Institute, Shenzhen, China
| | - Huangcan Li
- Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong
- Department of Otorhinolaryngology, Head and Neck Surgery, Chinese University of Hong Kong, Hong Kong City, Hong Kong
| | - Siu-Lung Ng
- Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong
| | - HeHai Jiang
- Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong
- Guangzhou Laboratory, Guangzhou, China
| | | | - Jufang He
- Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong
- City University of Hong Kong Shenzhen Research Institute, Shenzhen, China
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7
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Wolf D, Ayon-Olivas M, Sendtner M. BDNF-Regulated Modulation of Striatal Circuits and Implications for Parkinson's Disease and Dystonia. Biomedicines 2024; 12:1761. [PMID: 39200225 PMCID: PMC11351984 DOI: 10.3390/biomedicines12081761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 07/26/2024] [Accepted: 08/01/2024] [Indexed: 09/02/2024] Open
Abstract
Neurotrophins, particularly brain-derived neurotrophic factor (BDNF), act as key regulators of neuronal development, survival, and plasticity. BDNF is necessary for neuronal and functional maintenance in the striatum and the substantia nigra, both structures involved in the pathogenesis of Parkinson's Disease (PD). Depletion of BDNF leads to striatal degeneration and defects in the dendritic arborization of striatal neurons. Activation of tropomyosin receptor kinase B (TrkB) by BDNF is necessary for the induction of long-term potentiation (LTP), a form of synaptic plasticity, in the hippocampus and striatum. PD is characterized by the degeneration of nigrostriatal neurons and altered striatal plasticity has been implicated in the pathophysiology of PD motor symptoms, leading to imbalances in the basal ganglia motor pathways. Given its essential role in promoting neuronal survival and meditating synaptic plasticity in the motor system, BDNF might have an important impact on the pathophysiology of neurodegenerative diseases, such as PD. In this review, we focus on the role of BDNF in corticostriatal plasticity in movement disorders, including PD and dystonia. We discuss the mechanisms of how dopaminergic input modulates BDNF/TrkB signaling at corticostriatal synapses and the involvement of these mechanisms in neuronal function and synaptic plasticity. Evidence for alterations of BDNF and TrkB in PD patients and animal models are reviewed, and the potential of BDNF to act as a therapeutic agent is highlighted. Advancing our understanding of these mechanisms could pave the way toward innovative therapeutic strategies aiming at restoring neuroplasticity and enhancing motor function in these diseases.
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Affiliation(s)
| | | | - Michael Sendtner
- Institute of Clinical Neurobiology, University Hospital Wuerzburg, 97078 Wuerzburg, Germany (M.A.-O.)
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8
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Schmidt CC, Tong R, Emptage NJ. GluN2A- and GluN2B-containing pre-synaptic N-methyl-d-aspartate receptors differentially regulate action potential-evoked Ca 2+ influx via modulation of SK channels. Philos Trans R Soc Lond B Biol Sci 2024; 379:20230222. [PMID: 38853550 PMCID: PMC11343232 DOI: 10.1098/rstb.2023.0222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 12/07/2023] [Accepted: 01/02/2024] [Indexed: 06/11/2024] Open
Abstract
N-methyl-d-aspartate receptors (NMDARs) play a pivotal role in synaptic plasticity. While the functional role of post-synaptic NMDARs is well established, pre-synaptic NMDAR (pre-NMDAR) function is largely unexplored. Different pre-NMDAR subunit populations are documented at synapses, suggesting that subunit composition influences neuronal transmission. Here, we used electrophysiological recordings at Schaffer collateral-CA1 synapses partnered with Ca2+ imaging and glutamate uncaging at boutons of CA3 pyramidal neurones to reveal two populations of pre-NMDARs that contain either the GluN2A or GluN2B subunit. Activation of the GluN2B population decreases action potential-evoked Ca2+ influx via modulation of small-conductance Ca2+-activated K+ channels, while activation of the GluN2A population does the opposite. Critically, the level of functional expression of the subunits is subject to homeostatic regulation, bidirectionally affecting short-term facilitation, thus providing a capacity for a fine adjustment of information transfer. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
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Affiliation(s)
- Carla C. Schmidt
- Department of Pharmacology, University of Oxford, OxfordOX1 3QT, UK
| | - Rudi Tong
- Department of Pharmacology, University of Oxford, OxfordOX1 3QT, UK
- Montreal Neurological Institute, 3801 University Street, Montreal, QuebecH3A 2B4, Canada
| | - Nigel J. Emptage
- Department of Pharmacology, University of Oxford, OxfordOX1 3QT, UK
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9
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Buss EW, Jiang YQ, Santoro B, Brann DH, Nicholson DA, Siegelbaum SA, Sun Q. Regulation by Presynaptic NMDA Receptors of Non-Linear Postsynaptic Summation of the Cortical Input to CA1 Pyramidal Neurons. Neuroscience 2024:S0306-4522(24)00262-8. [PMID: 38878815 PMCID: PMC11638401 DOI: 10.1016/j.neuroscience.2024.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 06/02/2024] [Accepted: 06/09/2024] [Indexed: 06/24/2024]
Abstract
Entorhinal cortex (EC) LIII and LII glutamatergic neurons make monosynaptic connections onto distal apical dendrites of hippocampal CA1 and CA2 pyramidal neurons (PNs), respectively, through perforant path (PP) projections. We previously reported that a brief train of PP stimuli evokes strong supralinear temporal summation of excitatory postsynaptic potentials (EPSPs) in CA1 PNs that requires NMDAR activation, with relatively little summation in CA2 PNs in mice of either sex. Here we provide evidence from combined immunogold electron microscopy, cell-type specific genetic deletion and pharmacology that the NMDARs required for supralinear temporal summation of the CA1 PP EPSP are presynaptic, located in the PP terminals. Moreover, we found that the number of NMDARs in PP terminals innervating CA1 PNs is significantly greater than that found in PP terminals innervating CA2 PNs, providing a potential explanation for the difference in temporal summation in these two classes of hippocampal PNs.
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Affiliation(s)
- Eric W Buss
- Department of Neuroscience, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Yu-Qiu Jiang
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Bina Santoro
- Department of Neuroscience, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - David H Brann
- Department of Neuroscience, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Daniel A Nicholson
- Department of Neuroscience, Rush University Medical Center, Chicago, IL, USA
| | - Steven A Siegelbaum
- Department of Neuroscience, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
| | - Qian Sun
- Department of Neuroscience, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
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10
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Ugale V, Deshmukh R, Lokwani D, Narayana Reddy P, Khadse S, Chaudhari P, Kulkarni PP. GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics. Mol Divers 2024; 28:1765-1792. [PMID: 37266849 PMCID: PMC10234801 DOI: 10.1007/s11030-023-10656-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 05/10/2023] [Indexed: 06/03/2023]
Abstract
N-methyl-D-aspartate receptors (NMDARs) play essential roles in vital aspects of brain functions. NMDARs mediate clinical features of neurological diseases and thus, represent a potential therapeutic target for their treatments. Many findings implicated the GluN2B subunit of NMDARs in various neurological disorders including epilepsy, ischemic brain damage, and neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's chorea, and amyotrophic lateral sclerosis. Although a large amount of information is growing consistently on the importance of GluN2B subunit, however, limited recent data is available on how subunit-selective ligands impact NMDAR functions, which blunts the ability to render the diagnosis or craft novel treatments tailored to patients. To bridge this gap, we have focused on and summarized recently reported GluN2B selective ligands as emerging subunit-selective antagonists and modulators of NMDAR. Herein, we have also presented an overview of the structure-function relationship for potential GluN2B/NMDAR ligands with their binding sites and connection to CNS functionalities. Understanding of design rules and roles of GluN2B selective compounds will provide the link to medicinal chemists and neuroscientists to explore novel neurotherapeutic strategies against dysfunctions of glutamatergic neurotransmission.
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Affiliation(s)
- Vinod Ugale
- Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India.
- Bioprospecting Group, Agharkar Research Institute, Pune, Maharashtra, India.
| | - Rutuja Deshmukh
- Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India
| | - Deepak Lokwani
- Rajarshi Shahu College of Pharmacy, Buldana, Maharashtra, India
| | - P Narayana Reddy
- Department of Chemistry, School of Science, GITAM Deemed to be University, Hyderabad, India
| | - Saurabh Khadse
- Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India
| | - Prashant Chaudhari
- Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India
| | - Prasad P Kulkarni
- Bioprospecting Group, Agharkar Research Institute, Pune, Maharashtra, India.
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11
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Gould SA, Hodgson A, Clarke HF, Robbins TW, Roberts AC. Comparative Roles of the Caudate and Putamen in the Serial Order of Behavior: Effects of Striatal Glutamate Receptor Blockade on Variable versus Fixed Spatial Self-Ordered Sequencing in Marmosets. eNeuro 2024; 11:ENEURO.0541-23.2024. [PMID: 38471779 PMCID: PMC10964048 DOI: 10.1523/eneuro.0541-23.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/30/2024] [Accepted: 02/07/2024] [Indexed: 03/14/2024] Open
Abstract
Self-ordered sequencing is an important executive function involving planning and executing a series of steps to achieve goal-directed outcomes. The lateral frontal cortex is implicated in this behavior, but downstream striatal outputs remain relatively unexplored. We trained marmosets on a three-stimulus self-ordered spatial sequencing task using a touch-sensitive screen to explore the role of the caudate nucleus and putamen in random and fixed response arrays. By transiently blocking glutamatergic inputs to these regions, using intrastriatal CNQX microinfusions, we demonstrate that the caudate and putamen are both required for, but contribute differently to, flexible and fixed sequencing. CNQX into either the caudate or putamen impaired variable array accuracy, and infusions into both simultaneously elicited greater impairment. We demonstrated that continuous perseverative errors in variable array were caused by putamen infusions, likely due to interference with the putamen's established role in monitoring motor feedback. Caudate infusions, however, did not affect continuous errors, but did cause an upward trend in recurrent perseveration, possibly reflecting interference with the caudate's established role in spatial working memory and goal-directed planning. In contrast to variable array performance, while both caudate and putamen infusions impaired fixed array responding, the combined effects were not additive, suggesting possible competing roles. Infusions into either region individually, but not simultaneously, led to continuous perseveration. Recurrent perseveration in fixed arrays was caused by putamen, but not caudate, infusions. These results are consistent overall with a role of caudate in planning and flexible responding and the putamen in more rigid habitual or automatic responding.
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Affiliation(s)
- Stacey Anne Gould
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom
| | - Amy Hodgson
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom
| | - Hannah F Clarke
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom
| | - Trevor W Robbins
- Department of Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom
| | - Angela C Roberts
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom
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Bakhtazad A, Asgari Taei A, Parvizi F, Kadivar M, Farahmandfar M. Repeated pre-exposure to morphine inhibited the amnesic effect of ethanol on spatial memory: Involvement of CaMKII and BDNF. Alcohol 2024; 114:9-24. [PMID: 37597575 DOI: 10.1016/j.alcohol.2023.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 08/10/2023] [Accepted: 08/15/2023] [Indexed: 08/21/2023]
Abstract
Evidence has suggested that addiction and memory systems are related, but the signaling cascades underlying this interaction have not been completelyealed yet. The importance of calcium-calmodulin-dependent protein kinase II (CaMKII) and brain-derived neurotrophic factor (BDNF) in the memory processes and also in drug addiction has been previously established. In this present investigation, we examined the effects of repeated morphine pretreatment on impairment of spatial learning and memory acquisition induced by systemic ethanol administration in adult male rats. Also, we assessed how these drug exposures influence the expression level of CaMKII and BDNF in the hippocampus and amygdala. Animals were trained by a single training session of 8 trials, and a probe test containing a 60-s free-swim without a platform was administered 24 h later. Before training trials, rats were treated with a once-daily subcutaneous morphine injection for 3 days followed by a 5-day washout period. The results showed that pre-training ethanol (1 g/kg) impaired spatial learning and memory acquisition and down-regulated the mRNA expression of CaMKII and BDNF. The amnesic effect of ethanol was suppressed in morphine- (15 mg/kg/day) pretreated animals. Furthermore, the mRNA expression level of CaMKII and BDNF increased significantly following ethanol administration in morphine-pretreated rats. Conversely, this improvement in spatial memory acquisition was prevented by daily subcutaneous administration of naloxone (2 mg/kg) 15 min prior to morphine administration. Our findings suggest that sub-chronic morphine treatment reverses ethanol-induced spatial memory impairment, which could be explained by modulating CaMKII and BDNF mRNA expressions in the hippocampus and amygdala.
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Affiliation(s)
- Atefeh Bakhtazad
- Cellular and Molecular Research Center, Department of Neuroscience, Iran University of Medical Sciences, Tehran, Iran
| | - Afsaneh Asgari Taei
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Parvizi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Kadivar
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
| | - Maryam Farahmandfar
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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13
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Yu XB, Zhong KL, Chen C, Fu J, Chen F, Zhou HM, Zhang XH, Kim K, Pan JY. Simvastatin ameliorates synaptic plasticity impairment in chronic mild stress-induced depressed mice by modulating hippocampal NMDA receptor. Psychopharmacology (Berl) 2024; 241:75-88. [PMID: 37715015 DOI: 10.1007/s00213-023-06464-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 08/30/2023] [Indexed: 09/17/2023]
Abstract
BACKGROUND In our previous study, we showed simvastatin exerts an antidepressant effect and inhibits neuroinflammation. Given the role of synaptic impairment in depression development, we investigate the effect of simvastatin on synaptic plasticity in depression and the related mechanisms. METHODS Electrophysiological analysis, Golgi staining, and transmission electron microscope were performed to analyze the effect of simvastatin on synaptic impairment in depression. In addition, the localization and reactivity of N-methyl-D-aspartate receptor (NMDAR) subunits and the downstream signaling were investigated to explore the mechanism of simvastatin's effect on synaptic plasticity. RESULTS Simvastatin ameliorated the reduction of the magnitude of long-term potentiation (LTP) in Schaffer collateral-CA1, restored hippocampal dendritic spine density loss, improved the number of spine synapses, reversed the reduction in BrdU-positive cells in chronic mild stress (CMS)-induced depressed mice, and ameliorated NMDA-induced neurotoxicity in hippocampal neurons. Dysfunction of NMDAR activity in the hippocampus is associated with depression. Simvastatin treatment reversed the surface expression and phosphorylation changes of NMDAR subunits in NMDA-treated hippocampal neurons and depressed mice. In addition, simvastatin further increased the levels of mature BDNF, activating TrkB-Akt-mTOR signaling, which is critical for synaptic plasticity. CONCLUSIONS These findings suggest that simvastatin can improve the dysfunction of NMDAR and ameliorate hippocampal synaptic plasticity impairment in depressed mice.
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Affiliation(s)
- Xu-Ben Yu
- School of Pharmacy, Chonnam National University, Gwangju, South Korea.
- Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China.
- School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, People's Republic of China.
| | - Kai-Long Zhong
- Department of Pharmacy, Xiamen Clinical Research Center for Cancer Therapy, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, People's Republic of China
| | - Chuang Chen
- School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, People's Republic of China
| | - Jing Fu
- School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, People's Republic of China
| | - Fang Chen
- Department of Pharmacy, The First Affiliated Hospital of Xiamen University, Xiamen, 361005, People's Republic of China
| | - Hong-Min Zhou
- Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China
| | - Xiu-Hua Zhang
- Clinical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China
| | - Kwonseop Kim
- School of Pharmacy, Chonnam National University, Gwangju, South Korea.
| | - Jing-Ye Pan
- Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China.
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14
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Bertocchi I, Rocha-Almeida F, Romero-Barragán MT, Cambiaghi M, Carretero-Guillén A, Botta P, Dogbevia GK, Treviño M, Mele P, Oberto A, Larkum ME, Gruart A, Sprengel R, Delgado-García JM, Hasan MT. Pre- and postsynaptic N-methyl-D-aspartate receptors are required for sequential printing of fear memory engrams. iScience 2023; 26:108050. [PMID: 37876798 PMCID: PMC10590821 DOI: 10.1016/j.isci.2023.108050] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 07/24/2023] [Accepted: 09/22/2023] [Indexed: 10/26/2023] Open
Abstract
The organization of fear memory involves the participation of multiple brain regions. However, it is largely unknown how fear memory is formed, which circuit pathways are used for "printing" memory engrams across brain regions, and the role of identified brain circuits in memory retrieval. With advanced genetic methods, we combinatorially blocked presynaptic output and manipulated N-methyl-D-aspartate receptor (NMDAR) in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) before and after cued fear conditioning. Further, we tagged fear-activated neurons during associative learning for optogenetic memory recall. We found that presynaptic mPFC and postsynaptic BLA NMDARs are required for fear memory formation, but not expression. Our results provide strong evidence that NMDAR-dependent synaptic plasticity drives multi-trace systems consolidation for the sequential printing of fear memory engrams from BLA to mPFC and, subsequently, to the other regions, for flexible memory retrieval.
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Affiliation(s)
- Ilaria Bertocchi
- Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany
- Department of Neuroscience "Rita Levi Montalcini", Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, 10043 Turin, Italy
| | - Florbela Rocha-Almeida
- Division of Neurosciences, University Pablo de Olavide, Ctra. de Utrera, km. 1 41013 Seville, Spain
| | | | - Marco Cambiaghi
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Strada le Grazie 8, Verona, Italy
| | - Alejandro Carretero-Guillén
- Laboratory of Brain Circuits Therapeutics, Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Sede Building, Barrio Sarriena, s/n, 48940 Leioa, Spain
| | - Paolo Botta
- CNS drug development, Copenhagen, Capital Region, Denmark
| | - Godwin K. Dogbevia
- Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany
- Health Canada, 70 Colombine Driveway, Ottawa, ON K1A0K9, Canada
| | - Mario Treviño
- Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany
- Laboratorio de Plasticidad Cortical y Aprendizaje Perceptual, Instituto de Neurociencias, Universidad de Guadalajara, Guadalajara, Mexico
| | - Paolo Mele
- Department of Neuroscience "Rita Levi Montalcini", Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, 10043 Turin, Italy
| | - Alessandra Oberto
- Department of Neuroscience "Rita Levi Montalcini", Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, 10043 Turin, Italy
| | - Matthew E. Larkum
- NeuroCure, Charité-Universitatsmedizin, Virchowweg 6, 10117 Berlin, Germany
| | - Agnes Gruart
- Division of Neurosciences, University Pablo de Olavide, Ctra. de Utrera, km. 1 41013 Seville, Spain
| | - Rolf Sprengel
- Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany
| | | | - Mazahir T. Hasan
- Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany
- Laboratory of Brain Circuits Therapeutics, Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Sede Building, Barrio Sarriena, s/n, 48940 Leioa, Spain
- Ikerbasque – Basque Foundation for Science, Bilbao, Spain
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15
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Xie RG, Xu GY, Wu SX, Luo C. Presynaptic glutamate receptors in nociception. Pharmacol Ther 2023; 251:108539. [PMID: 37783347 DOI: 10.1016/j.pharmthera.2023.108539] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/19/2023] [Accepted: 09/25/2023] [Indexed: 10/04/2023]
Abstract
Chronic pain is a frequent, distressing and poorly understood health problem. Plasticity of synaptic transmission in the nociceptive pathways after inflammation or injury is assumed to be an important cellular basis for chronic, pathological pain. Glutamate serves as the main excitatory neurotransmitter at key synapses in the somatosensory nociceptive pathways, in which it acts on both ionotropic and metabotropic glutamate receptors. Although conventionally postsynaptic, compelling anatomical and physiological evidence demonstrates the presence of presynaptic glutamate receptors in the nociceptive pathways. Presynaptic glutamate receptors play crucial roles in nociceptive synaptic transmission and plasticity. They modulate presynaptic neurotransmitter release and synaptic plasticity, which in turn regulates pain sensitization. In this review, we summarize the latest understanding of the expression of presynaptic glutamate receptors in the nociceptive pathways, and how they contribute to nociceptive information processing and pain hypersensitivity associated with inflammation / injury. We uncover the cellular and molecular mechanisms of presynaptic glutamate receptors in shaping synaptic transmission and plasticity to mediate pain chronicity, which may provide therapeutic approaches for treatment of chronic pain.
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Affiliation(s)
- Rou-Gang Xie
- Department of Neurobiology, Fourth Military Medical University, Xi'an 710032, China.
| | - Guang-Yin Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou 215123, China
| | - Sheng-Xi Wu
- Department of Neurobiology, Fourth Military Medical University, Xi'an 710032, China.
| | - Ceng Luo
- Department of Neurobiology, Fourth Military Medical University, Xi'an 710032, China.
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16
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Blackwell KT, Doya K. Enhancing reinforcement learning models by including direct and indirect pathways improves performance on striatal dependent tasks. PLoS Comput Biol 2023; 19:e1011385. [PMID: 37594982 PMCID: PMC10479916 DOI: 10.1371/journal.pcbi.1011385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/05/2023] [Accepted: 07/25/2023] [Indexed: 08/20/2023] Open
Abstract
A major advance in understanding learning behavior stems from experiments showing that reward learning requires dopamine inputs to striatal neurons and arises from synaptic plasticity of cortico-striatal synapses. Numerous reinforcement learning models mimic this dopamine-dependent synaptic plasticity by using the reward prediction error, which resembles dopamine neuron firing, to learn the best action in response to a set of cues. Though these models can explain many facets of behavior, reproducing some types of goal-directed behavior, such as renewal and reversal, require additional model components. Here we present a reinforcement learning model, TD2Q, which better corresponds to the basal ganglia with two Q matrices, one representing direct pathway neurons (G) and another representing indirect pathway neurons (N). Unlike previous two-Q architectures, a novel and critical aspect of TD2Q is to update the G and N matrices utilizing the temporal difference reward prediction error. A best action is selected for N and G using a softmax with a reward-dependent adaptive exploration parameter, and then differences are resolved using a second selection step applied to the two action probabilities. The model is tested on a range of multi-step tasks including extinction, renewal, discrimination; switching reward probability learning; and sequence learning. Simulations show that TD2Q produces behaviors similar to rodents in choice and sequence learning tasks, and that use of the temporal difference reward prediction error is required to learn multi-step tasks. Blocking the update rule on the N matrix blocks discrimination learning, as observed experimentally. Performance in the sequence learning task is dramatically improved with two matrices. These results suggest that including additional aspects of basal ganglia physiology can improve the performance of reinforcement learning models, better reproduce animal behaviors, and provide insight as to the role of direct- and indirect-pathway striatal neurons.
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Affiliation(s)
- Kim T Blackwell
- Department of Bioengineering, Volgenau School of Engineering, George Mason University, Fairfax, Virginia, United States of America
| | - Kenji Doya
- Neural Computation Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
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17
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Schellino R, Besusso D, Parolisi R, Gómez-González GB, Dallere S, Scaramuzza L, Ribodino M, Campus I, Conforti P, Parmar M, Boido M, Cattaneo E, Buffo A. hESC-derived striatal progenitors grafted into a Huntington's disease rat model support long-term functional motor recovery by differentiating, self-organizing and connecting into the lesioned striatum. Stem Cell Res Ther 2023; 14:189. [PMID: 37507794 PMCID: PMC10386300 DOI: 10.1186/s13287-023-03422-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Huntington's disease (HD) is a motor and cognitive neurodegenerative disorder due to prominent loss of striatal medium spiny neurons (MSNs). Cell replacement using human embryonic stem cells (hESCs) derivatives may offer new therapeutic opportunities to replace degenerated neurons and repair damaged circuits. METHODS With the aim to develop effective cell replacement for HD, we assessed the long-term therapeutic value of hESC-derived striatal progenitors by grafting the cells into the striatum of a preclinical model of HD [i.e., adult immunodeficient rats in which the striatum was lesioned by monolateral injection of quinolinic acid (QA)]. We examined the survival, maturation, self-organization and integration of the graft as well as its impact on lesion-dependent motor alterations up to 6 months post-graft. Moreover, we tested whether exposing a cohort of QA-lesioned animals to environmental enrichment (EE) could improve graft integration and function. RESULTS Human striatal progenitors survived up to 6 months after transplantation and showed morphological and neurochemical features typical of human MSNs. Donor-derived interneurons were also detected. Grafts wired in both local and long-range striatal circuits, formed domains suggestive of distinct ganglionic eminence territories and displayed emerging striosome features. Moreover, over time grafts improved complex motor performances affected by QA. EE selectively increased cell differentiation into MSN phenotype and promoted host-to-graft connectivity. However, when combined to the graft, the EE paradigm used in this study was insufficient to produce an additive effect on task execution. CONCLUSIONS The data support the long-term therapeutic potential of ESC-derived human striatal progenitor grafts for the replacement of degenerated striatal neurons in HD and suggest that EE can effectively accelerate the maturation and promote the integration of human striatal cells.
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Affiliation(s)
- Roberta Schellino
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, 10126, Turin, Italy.
- Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043, Orbassano, Italy.
| | - Dario Besusso
- Department of Biosciences, University of Milan, 20122, Milan, Italy
- National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", 20133, Milan, Italy
| | - Roberta Parolisi
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, 10126, Turin, Italy
- Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043, Orbassano, Italy
| | - Gabriela B Gómez-González
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, 10126, Turin, Italy
- Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043, Orbassano, Italy
| | - Sveva Dallere
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, 10126, Turin, Italy
- Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043, Orbassano, Italy
| | - Linda Scaramuzza
- Department of Biosciences, University of Milan, 20122, Milan, Italy
- National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", 20133, Milan, Italy
| | - Marta Ribodino
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, 10126, Turin, Italy
- Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043, Orbassano, Italy
| | - Ilaria Campus
- Department of Biosciences, University of Milan, 20122, Milan, Italy
- National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", 20133, Milan, Italy
| | - Paola Conforti
- Department of Biosciences, University of Milan, 20122, Milan, Italy
- National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", 20133, Milan, Italy
| | - Malin Parmar
- Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 22184, Lund, Sweden
| | - Marina Boido
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, 10126, Turin, Italy
- Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043, Orbassano, Italy
| | - Elena Cattaneo
- Department of Biosciences, University of Milan, 20122, Milan, Italy
- National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", 20133, Milan, Italy
| | - Annalisa Buffo
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, 10126, Turin, Italy.
- Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043, Orbassano, Italy.
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18
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Vitet H, Bruyère J, Xu H, Séris C, Brocard J, Abada YS, Delatour B, Scaramuzzino C, Venance L, Saudou F. Huntingtin recruits KIF1A to transport synaptic vesicle precursors along the mouse axon to support synaptic transmission and motor skill learning. eLife 2023; 12:e81011. [PMID: 37431882 PMCID: PMC10365837 DOI: 10.7554/elife.81011] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 07/06/2023] [Indexed: 07/12/2023] Open
Abstract
Neurotransmitters are released at synapses by synaptic vesicles (SVs), which originate from SV precursors (SVPs) that have traveled along the axon. Because each synapse maintains a pool of SVs, only a small fraction of which are released, it has been thought that axonal transport of SVPs does not affect synaptic function. Here, studying the corticostriatal network both in microfluidic devices and in mice, we find that phosphorylation of the Huntingtin protein (HTT) increases axonal transport of SVPs and synaptic glutamate release by recruiting the kinesin motor KIF1A. In mice, constitutive HTT phosphorylation causes SV over-accumulation at synapses, increases the probability of SV release, and impairs motor skill learning on the rotating rod. Silencing KIF1A in these mice restored SV transport and motor skill learning to wild-type levels. Axonal SVP transport within the corticostriatal network thus influences synaptic plasticity and motor skill learning.
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Affiliation(s)
- Hélène Vitet
- Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut NeuroscienceGrenobleFrance
| | - Julie Bruyère
- Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut NeuroscienceGrenobleFrance
| | - Hao Xu
- Center for Interdisciplinary Research in Biology, College de France, CNRS, INSERM, Université PSLParisFrance
| | - Claire Séris
- Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut NeuroscienceGrenobleFrance
| | - Jacques Brocard
- Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut NeuroscienceGrenobleFrance
| | - Yah-Sé Abada
- Sorbonne Université, Institut du Cerveau, Paris Brain Institute, ICM, Inserm U1127, CNRS UMR7225ParisFrance
| | - Benoît Delatour
- Sorbonne Université, Institut du Cerveau, Paris Brain Institute, ICM, Inserm U1127, CNRS UMR7225ParisFrance
| | - Chiara Scaramuzzino
- Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut NeuroscienceGrenobleFrance
| | - Laurent Venance
- Center for Interdisciplinary Research in Biology, College de France, CNRS, INSERM, Université PSLParisFrance
| | - Frédéric Saudou
- Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut NeuroscienceGrenobleFrance
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19
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Andreska T, Lüningschrör P, Wolf D, McFleder RL, Ayon-Olivas M, Rattka M, Drechsler C, Perschin V, Blum R, Aufmkolk S, Granado N, Moratalla R, Sauer M, Monoranu C, Volkmann J, Ip CW, Stigloher C, Sendtner M. DRD1 signaling modulates TrkB turnover and BDNF sensitivity in direct pathway striatal medium spiny neurons. Cell Rep 2023; 42:112575. [PMID: 37252844 DOI: 10.1016/j.celrep.2023.112575] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 03/09/2023] [Accepted: 05/14/2023] [Indexed: 06/01/2023] Open
Abstract
Disturbed motor control is a hallmark of Parkinson's disease (PD). Cortico-striatal synapses play a central role in motor learning and adaption, and brain-derived neurotrophic factor (BDNF) from cortico-striatal afferents modulates their plasticity via TrkB in striatal medium spiny projection neurons (SPNs). We studied the role of dopamine in modulating the sensitivity of direct pathway SPNs (dSPNs) to BDNF in cultures of fluorescence-activated cell sorting (FACS)-enriched D1-expressing SPNs and 6-hydroxydopamine (6-OHDA)-treated rats. DRD1 activation causes enhanced TrkB translocation to the cell surface and increased sensitivity for BDNF. In contrast, dopamine depletion in cultured dSPN neurons, 6-OHDA-treated rats, and postmortem brain of patients with PD reduces BDNF responsiveness and causes formation of intracellular TrkB clusters. These clusters associate with sortilin related VPS10 domain containing receptor 2 (SORCS-2) in multivesicular-like structures, which apparently protects them from lysosomal degradation. Thus, impaired TrkB processing might contribute to disturbed motor function in PD.
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Affiliation(s)
- Thomas Andreska
- Institute of Clinical Neurobiology, University Hospital Wuerzburg, 97078 Wuerzburg, Germany
| | - Patrick Lüningschrör
- Institute of Clinical Neurobiology, University Hospital Wuerzburg, 97078 Wuerzburg, Germany
| | - Daniel Wolf
- Institute of Clinical Neurobiology, University Hospital Wuerzburg, 97078 Wuerzburg, Germany
| | - Rhonda L McFleder
- Department of Neurology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany
| | - Maurilyn Ayon-Olivas
- Institute of Clinical Neurobiology, University Hospital Wuerzburg, 97078 Wuerzburg, Germany
| | - Marta Rattka
- Department of Neurology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany
| | - Christine Drechsler
- Department of Microbiology, Biocenter, Julius-Maximilians-University Wuerzburg, 97074 Wuerzburg, Germany
| | - Veronika Perschin
- Imaging Core Facility of the Biocenter, Julius-Maximilians-University Wuerzburg, 97074 Wuerzburg, Germany
| | - Robert Blum
- Department of Neurology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany
| | - Sarah Aufmkolk
- Department of Biotechnology and Biophysics, Julius-Maximilians-University Wuerzburg, 97074 Wuerzburg, Germany; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Noelia Granado
- Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, 28002 Madrid, Spain
| | - Rosario Moratalla
- Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, 28002 Madrid, Spain
| | - Markus Sauer
- Department of Biotechnology and Biophysics, Julius-Maximilians-University Wuerzburg, 97074 Wuerzburg, Germany
| | - Camelia Monoranu
- Department for Neuropathology, Julius-Maximilians-University Wuerzburg, 97080 Wuerzburg, Germany
| | - Jens Volkmann
- Department of Neurology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany
| | - Chi Wang Ip
- Department of Neurology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany
| | - Christian Stigloher
- Imaging Core Facility of the Biocenter, Julius-Maximilians-University Wuerzburg, 97074 Wuerzburg, Germany
| | - Michael Sendtner
- Institute of Clinical Neurobiology, University Hospital Wuerzburg, 97078 Wuerzburg, Germany.
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20
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Olivero G, Grilli M, Marchi M, Pittaluga A. Metamodulation of presynaptic NMDA receptors: New perspectives for pharmacological interventions. Neuropharmacology 2023; 234:109570. [PMID: 37146939 DOI: 10.1016/j.neuropharm.2023.109570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/26/2023] [Accepted: 05/02/2023] [Indexed: 05/07/2023]
Abstract
Metamodulation shifted the scenario of the central neuromodulation from a simplified unimodal model to a multimodal one. It involves different receptors/membrane proteins physically associated or merely colocalized that act in concert to control the neuronal functions influencing each other. Defects or maladaptation of metamodulation would subserve neuropsychiatric disorders or even synaptic adaptations relevant to drug dependence. Therefore, this "vulnerability" represents a main issue to be deeply analyzed to predict its aetiopathogenesis, but also to propose targeted pharmaceutical interventions. The review focusses on presynaptic release-regulating NMDA receptors and on some of the mechanisms of their metamodulation described in the literature. Attention is paid to the interactors, including both ionotropic and metabotropic receptors, transporters and intracellular proteins, which metamodulate their responsiveness in physiological conditions but also undergo adaptation that are relevant to neurological dysfunctions. All these structures are attracting more and more the interest as promising druggable targets for the treatment of NMDAR-related central diseases: these substances would not exert on-off control of the colocalized NMDA receptors (as usually observed with NMDAR full agonists/antagonists), but rather modulate their functions, with the promise of limiting side effects that would favor their translation from preclinic to clinic.
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Affiliation(s)
- Guendalina Olivero
- Department of Pharmacy, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy
| | - Massimo Grilli
- Department of Pharmacy, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy; Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), 16148, Genoa, Italy.
| | - Mario Marchi
- Department of Pharmacy, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy
| | - Anna Pittaluga
- Department of Pharmacy, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy; Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), 16148, Genoa, Italy
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21
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Arévalo JC, Deogracias R. Mechanisms Controlling the Expression and Secretion of BDNF. Biomolecules 2023; 13:biom13050789. [PMID: 37238659 DOI: 10.3390/biom13050789] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/19/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
Brain-derived nerve factor (BDNF), through TrkB receptor activation, is an important modulator for many different physiological and pathological functions in the nervous system. Among them, BDNF plays a crucial role in the development and correct maintenance of brain circuits and synaptic plasticity as well as in neurodegenerative diseases. The proper functioning of the central nervous system depends on the available BDNF concentrations, which are tightly regulated at transcriptional and translational levels but also by its regulated secretion. In this review we summarize the new advances regarding the molecular players involved in BDNF release. In addition, we will address how changes of their levels or function in these proteins have a great impact in those functions modulated by BDNF under physiological and pathological conditions.
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Affiliation(s)
- Juan Carlos Arévalo
- Department of Cell Biology and Pathology, Institute of Neurosciences of Castille and Leon (INCyL), University of Salamanca, 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Rubén Deogracias
- Department of Cell Biology and Pathology, Institute of Neurosciences of Castille and Leon (INCyL), University of Salamanca, 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
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22
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Liao GY, Xu H, Shumate J, Scampavia L, Spicer T, Xu B. High throughput assay for compounds that boost BDNF expression in neurons. SLAS DISCOVERY : ADVANCING LIFE SCIENCES R & D 2023; 28:88-94. [PMID: 36842668 PMCID: PMC10759152 DOI: 10.1016/j.slasd.2023.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/30/2023] [Accepted: 02/21/2023] [Indexed: 02/27/2023]
Abstract
Deficiencies in brain-derived neurotrophic factor (BDNF) have been linked to several brain disorders, making compounds that can boost neuronal BDNF synthesis attractive as potential therapeutics. However, a sensitive and quantitative BDNF assay for high-throughput screening (HTS) is still missing. Here we report the generation of a new mouse Bdnf allele, BdnfNLuc, in which the sequence encoding nano luciferase (NLuc) is inserted into the Bdnf locus immediately before the stop codon so that the allele will produce a BDNF-NLuc fusion protein. BDNF-NLuc protein appears to function like BDNF as BdnfNLuc/NLuc homozygous mice grew and behaved almost normally. We were able to establish and optimize cultures of cortical and hippocampal BdnfNLuc/+ neurons isolated from mouse embryos in 384-well plates. We used the cultures as a phenotypic assay to detect the ability of 10 mM KCl to stimulate BDNF synthesis and achieved a reproducible Z' factor > 0.50 for the assay, a measure considered suitable for HTS. We successfully scaled up the assay to screen the 1280-compound LOPAC library (Library of Pharmacologically Active Compounds). The screen identified several BDNF-boosting compounds, one of which is Bay K8644, a L-type voltage-gated calcium channel (L-VGCC) agonist, which was previously shown to stimulate BDNF synthesis. These results indicate that our phenotypic neuronal assay is ready for HTS to identify novel BDNF-boosting compounds.
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Affiliation(s)
- Guey-Ying Liao
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Haifei Xu
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Justin Shumate
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Louis Scampavia
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Timothy Spicer
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Baoji Xu
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, 130 Scripps Way, Jupiter, FL 33458, USA.
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23
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Caubit X, Gubellini P, Roubertoux PL, Carlier M, Molitor J, Chabbert D, Metwaly M, Salin P, Fatmi A, Belaidouni Y, Brosse L, Kerkerian-Le Goff L, Fasano L. Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors. Transl Psychiatry 2022; 12:106. [PMID: 35292625 PMCID: PMC8924251 DOI: 10.1038/s41398-022-01865-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 02/18/2022] [Accepted: 02/24/2022] [Indexed: 01/15/2023] Open
Abstract
We previously linked TSHZ3 haploinsufficiency to autism spectrum disorder (ASD) and showed that embryonic or postnatal Tshz3 deletion in mice results in behavioral traits relevant to the two core domains of ASD, namely social interaction deficits and repetitive behaviors. Here, we provide evidence that cortical projection neurons (CPNs) and striatal cholinergic interneurons (SCINs) are two main and complementary players in the TSHZ3-linked ASD syndrome. In the cerebral cortex, TSHZ3 is expressed in CPNs and in a proportion of GABAergic interneurons, but not in cholinergic interneurons or glial cells. In the striatum, TSHZ3 is expressed in all SCINs, while its expression is absent or partial in the other main brain cholinergic systems. We then characterized two new conditional knockout (cKO) models generated by crossing Tshz3flox/flox with Emx1-Cre (Emx1-cKO) or Chat-Cre (Chat-cKO) mice to decipher the respective role of CPNs and SCINs. Emx1-cKO mice show altered excitatory synaptic transmission onto CPNs and impaired plasticity at corticostriatal synapses, with neither cortical neuron loss nor abnormal layer distribution. These animals present social interaction deficits but no repetitive patterns of behavior. Chat-cKO mice exhibit no loss of SCINs but changes in the electrophysiological properties of these interneurons, associated with repetitive patterns of behavior without social interaction deficits. Therefore, dysfunction in either CPNs or SCINs segregates with a distinct ASD behavioral trait. These findings provide novel insights onto the implication of the corticostriatal circuitry in ASD by revealing an unexpected neuronal dichotomy in the biological background of the two core behavioral domains of this disorder.
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Affiliation(s)
- Xavier Caubit
- grid.462081.90000 0004 0598 4854Aix-Marseille Univ, CNRS, IBDM, UMR7288 Marseille, France
| | - Paolo Gubellini
- grid.462081.90000 0004 0598 4854Aix-Marseille Univ, CNRS, IBDM, UMR7288 Marseille, France
| | - Pierre L. Roubertoux
- grid.5399.60000 0001 2176 4817Aix-Marseille Univ, INSERM, MMG, UMR1251 Marseille, France
| | - Michèle Carlier
- grid.463724.00000 0004 0385 2989Aix-Marseille Univ, CNRS, LPC, UMR7290 Marseille, France
| | - Jordan Molitor
- grid.462081.90000 0004 0598 4854Aix-Marseille Univ, CNRS, IBDM, UMR7288 Marseille, France
| | - Dorian Chabbert
- grid.462081.90000 0004 0598 4854Aix-Marseille Univ, CNRS, IBDM, UMR7288 Marseille, France
| | - Mehdi Metwaly
- grid.462081.90000 0004 0598 4854Aix-Marseille Univ, CNRS, IBDM, UMR7288 Marseille, France
| | - Pascal Salin
- grid.462081.90000 0004 0598 4854Aix-Marseille Univ, CNRS, IBDM, UMR7288 Marseille, France
| | - Ahmed Fatmi
- grid.462081.90000 0004 0598 4854Aix-Marseille Univ, CNRS, IBDM, UMR7288 Marseille, France
| | - Yasmine Belaidouni
- grid.462081.90000 0004 0598 4854Aix-Marseille Univ, CNRS, IBDM, UMR7288 Marseille, France
| | - Lucie Brosse
- grid.462081.90000 0004 0598 4854Aix-Marseille Univ, CNRS, IBDM, UMR7288 Marseille, France
| | | | - Laurent Fasano
- Aix-Marseille Univ, CNRS, IBDM, UMR7288, Marseille, France.
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24
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R Stewart AF, Chen HH. N-methyl-D-aspartate receptor functions altered by neuronal PTP1B activation in Alzheimer's disease and schizophrenia models. Neural Regen Res 2022; 17:2208-2210. [PMID: 35259833 PMCID: PMC9083166 DOI: 10.4103/1673-5374.335793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Alexandre F R Stewart
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and University of Ottawa Heart Institute; Centre for Infection, Immunity and Inflammation, Ottawa, ON, Canada
| | - Hsiao-Huei Chen
- Centre for Infection, Immunity and Inflammation; Medicine, Cellular and Molecular Medicine, University of Ottawa Brain and Mind Institute, Ottawa Hospital Research Institute, Ottawa, ON, Canada
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25
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Xie RG, Chu WG, Liu DL, Wang X, Ma SB, Wang F, Wang FD, Lin Z, Wu WB, Lu N, Liu YY, Han WJ, Zhang H, Bai ZT, Hu SJ, Tao HR, Kuner T, Zhang X, Kuner R, Wu SX, Luo C. Presynaptic NMDARs on spinal nociceptor terminals state-dependently modulate synaptic transmission and pain. Nat Commun 2022; 13:728. [PMID: 35132099 PMCID: PMC8821657 DOI: 10.1038/s41467-022-28429-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 01/21/2022] [Indexed: 12/24/2022] Open
Abstract
Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. However, how presynaptic NMDARs (PreNMDARs) in spinal nociceptor terminals control presynaptic plasticity and pain hypersensitivity has remained unclear. Here we report that PreNMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner. PreNMDARs depresses presynaptic transmission in basal state, while paradoxically causing presynaptic potentiation upon injury. This state-dependent modulation is dependent on Ca2+ influx via PreNMDARs. Small conductance Ca2+-activated K+ (SK) channels are responsible for PreNMDARs-mediated synaptic depression. Rather, tissue inflammation induces PreNMDARs-PKG-I-dependent BDNF secretion from spinal nociceptor terminals, leading to SK channels downregulation, which in turn converts presynaptic depression to potentiation. Our findings shed light on the state-dependent characteristics of PreNMDARs in spinal nociceptor terminals on modulating nociceptive transmission and revealed a mechanism underlying state-dependent transition. Moreover, we identify PreNMDARs in spinal nociceptor terminals as key constituents of activity-dependent pain sensitization. Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. Here, the authors show that also presynaptic NMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner.
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26
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Gao WJ, Yang SS, Mack NR, Chamberlin LA. Aberrant maturation and connectivity of prefrontal cortex in schizophrenia-contribution of NMDA receptor development and hypofunction. Mol Psychiatry 2022; 27:731-743. [PMID: 34163013 PMCID: PMC8695640 DOI: 10.1038/s41380-021-01196-w] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 06/02/2021] [Accepted: 06/10/2021] [Indexed: 02/06/2023]
Abstract
The neurobiology of schizophrenia involves multiple facets of pathophysiology, ranging from its genetic basis over changes in neurochemistry and neurophysiology, to the systemic level of neural circuits. Although the precise mechanisms associated with the neuropathophysiology remain elusive, one essential aspect is the aberrant maturation and connectivity of the prefrontal cortex that leads to complex symptoms in various stages of the disease. Here, we focus on how early developmental dysfunction, especially N-methyl-D-aspartate receptor (NMDAR) development and hypofunction, may lead to the dysfunction of both local circuitry within the prefrontal cortex and its long-range connectivity. More specifically, we will focus on an "all roads lead to Rome" hypothesis, i.e., how NMDAR hypofunction during development acts as a convergence point and leads to local gamma-aminobutyric acid (GABA) deficits and input-output dysconnectivity in the prefrontal cortex, which eventually induce cognitive and social deficits. Many outstanding questions and hypothetical mechanisms are listed for future investigations of this intriguing hypothesis that may lead to a better understanding of the aberrant maturation and connectivity associated with the prefrontal cortex.
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Affiliation(s)
- Wen-Jun Gao
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, 19129, USA.
| | - Sha-Sha Yang
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, 19129, USA
| | - Nancy R Mack
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, 19129, USA
| | - Linda A Chamberlin
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, 19129, USA
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27
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Kochi C, Salvi A, Atrooz F, Salim S. Simulated vehicle exhaust exposure induces sex-dependent behavioral deficits in rats. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2021; 86:103660. [PMID: 33865999 DOI: 10.1016/j.etap.2021.103660] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 04/05/2021] [Accepted: 04/12/2021] [Indexed: 06/12/2023]
Abstract
Chronic exposure to vehicle exhaust emissions are known to cause several adverse health effects. In this study, we examined the impact of several parameters of behavioral, cardiovascular and biochemical functions upon exposure of pro-oxidants CO2, NO2 and CO (simulated vehicle exhaust exposure: SVEE) in male and female rats. Adult rats were subjected to SVEE or ambient air in whole body chambers (5 h/day, 2 weeks). Male, but not female, rats developed memory deficits, and exhibited anxiety- and depression-like behavior, accompanied with significantly high levels of serum corticosterone, oxidative stress, and inflammatory markers (CRP and TNFα), associated with lower levels of total antioxidant capacity, glutathione, glyoxalase and superoxide dismutase (SOD) activities. Brain region-specific downregulation of Cu/Zn SOD, Mn SOD, GSR, PKCα, ERK1/2, CaMKIV, CREB, BDNF and NMDAR subunit protein expression were also observed in male, but not female, rats. Blood pressure, heart rate and eGFR were not negatively impacted by SVEE. Our results suggest that SVEE, through its pro-oxidant content, induces oxido-inflammation in susceptible brain regions in a sex-dependent manner.
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Affiliation(s)
- Camila Kochi
- Department of Pharmacological & Pharmaceutical Sciences, University of Houston, Houston, TX, United States
| | - Ankita Salvi
- Translational Medicine Department, QPS, LLC, Newark, DE, United States
| | - Fatin Atrooz
- Department of Pharmacological & Pharmaceutical Sciences, University of Houston, Houston, TX, United States
| | - Samina Salim
- Department of Pharmacological & Pharmaceutical Sciences, University of Houston, Houston, TX, United States.
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28
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Lituma PJ, Kwon HB, Alviña K, Luján R, Castillo PE. Presynaptic NMDA receptors facilitate short-term plasticity and BDNF release at hippocampal mossy fiber synapses. eLife 2021; 10:e66612. [PMID: 34061025 PMCID: PMC8186907 DOI: 10.7554/elife.66612] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 05/28/2021] [Indexed: 01/12/2023] Open
Abstract
Neurotransmitter release is a highly controlled process by which synapses can critically regulate information transfer within neural circuits. While presynaptic receptors - typically activated by neurotransmitters and modulated by neuromodulators - provide a powerful way of fine-tuning synaptic function, their contribution to activity-dependent changes in transmitter release remains poorly understood. Here, we report that presynaptic NMDA receptors (preNMDARs) at mossy fiber boutons in the rodent hippocampus can be activated by physiologically relevant patterns of activity and selectively enhance short-term synaptic plasticity at mossy fiber inputs onto CA3 pyramidal cells and mossy cells, but not onto inhibitory interneurons. Moreover, preNMDARs facilitate brain-derived neurotrophic factor release and contribute to presynaptic calcium rise. Taken together, our results indicate that by increasing presynaptic calcium, preNMDARs fine-tune mossy fiber neurotransmission and can control information transfer during dentate granule cell burst activity that normally occur in vivo.
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Affiliation(s)
- Pablo J Lituma
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of MedicineBronxUnited States
| | - Hyung-Bae Kwon
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of MedicineBronxUnited States
| | - Karina Alviña
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of MedicineBronxUnited States
| | - Rafael Luján
- Instituto de Investigación en Discapacidades Neurológicas (IDINE), Facultad de Medicina, Universidad Castilla-La ManchaAlbaceteSpain
| | - Pablo E Castillo
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of MedicineBronxUnited States
- Department of Psychiatry and Behavioral Sciences, Albert Einstein College of MedicineBronxUnited States
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29
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Zhang L, Qin Z, Sharmin F, Lin W, Ricke KM, Zasloff MA, Stewart AFR, Chen HH. Tyrosine phosphatase PTP1B impairs presynaptic NMDA receptor-mediated plasticity in a mouse model of Alzheimer's disease. Neurobiol Dis 2021; 156:105402. [PMID: 34044147 DOI: 10.1016/j.nbd.2021.105402] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/29/2021] [Accepted: 05/21/2021] [Indexed: 12/11/2022] Open
Abstract
Mutations in the beta-amyloid protein (APP) cause familial Alzheimer's disease. In hAPP-J20 mice expressing mutant APP, pharmacological inhibition or genetic ablation of the tyrosine phosphatase PTP1B prevents CA3 hippocampus neuron loss and cognitive decline. However, how targeting PTP1B affects the cellular mechanisms underlying these cognitive deficits remains unknown. Changes in synaptic strength at the hippocampus can affect information processing for learning and memory. While prior studies have focused on post-synaptic mechanisms to account for synaptic deficits in Alzheimer's disease models, presynaptic mechanisms may also be affected. Here, using whole cell patch-clamp recording, coefficient of variation (CV) analysis suggested a profound presynaptic deficit in long-term potentiation (LTP) of CA3:CA1 synapses in hAPP-J20 mice. While the membrane-impermeable ionotropic NMDA receptor (NMDAR) blocker norketamine in the post-synaptic recording electrode had no effect on LTP, additional bath application of the ionotropic NMDAR blockers MK801 could replicate the deficit in LTP in wild type mice. In contrast to LTP, the paired-pulse ratio and short-term facilitation (STF) were aberrantly increased in hAPP-J20 mice. These synaptic deficits in hAPP-J20 mice were associated with reduced phosphorylation of NMDAR GluN2B and the synaptic vesicle recycling protein NSF (N-ethylmaleimide sensitive factor). Phosphorylation of both proteins, together with synaptic plasticity and cognitive function, were restored by PTP1B ablation or inhibition by the PTP1B-selective inhibitor Trodusquemine. Taken together, our results indicate that PTP1B impairs presynaptic NMDAR-mediated synaptic plasticity required for spatial learning in a mouse model of Alzheimer's disease. Since Trodusquemine has undergone phase 1/2 clinical trials to treat obesity, it could be repurposed to treat Alzheimer's disease.
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Affiliation(s)
- Li Zhang
- Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada; University of Ottawa Brain and Mind Institute, Ottawa, ON K1H8M5, Canada
| | - Zhaohong Qin
- Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada; University of Ottawa Brain and Mind Institute, Ottawa, ON K1H8M5, Canada
| | - Fariba Sharmin
- Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada; University of Ottawa Brain and Mind Institute, Ottawa, ON K1H8M5, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Wei Lin
- Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada; University of Ottawa Brain and Mind Institute, Ottawa, ON K1H8M5, Canada
| | - Konrad M Ricke
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; University of Ottawa Heart Institute, Ottawa, ON K1Y4W7, Canada
| | - Michael A Zasloff
- Georgetown University School of Medicine, MedStar Georgetown Transplant Institute, Washington, DC, 2007, USA
| | - Alexandre F R Stewart
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; University of Ottawa Heart Institute, Ottawa, ON K1Y4W7, Canada.
| | - Hsiao-Huei Chen
- Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada; University of Ottawa Brain and Mind Institute, Ottawa, ON K1H8M5, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Department of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
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30
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Nociceptor-localized cGMP-dependent protein kinase I is a critical generator for central sensitization and neuropathic pain. Pain 2021; 162:135-151. [PMID: 32773598 DOI: 10.1097/j.pain.0000000000002013] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Patients with neuropathic pain often experience exaggerated pain and anxiety. Central sensitization has been linked with the maintenance of neuropathic pain and may become an autonomous pain generator. Conversely, emerging evidence accumulated that central sensitization is initiated and maintained by ongoing nociceptive primary afferent inputs. However, it remains elusive what mechanisms underlie this phenomenon and which peripheral candidate contributes to central sensitization that accounts for pain hypersensitivity and pain-related anxiety. Previous studies have implicated peripherally localized cGMP-dependent protein kinase I (PKG-I) in plasticity of nociceptors and spinal synaptic transmission as well as inflammatory hyperalgesia. However, whether peripheral PKG-I contributes to cortical plasticity and hence maintains nerve injury-induced pain hypersensitivity and anxiety is unknown. Here, we demonstrated significant upregulation of PKG-I in ipsilateral L3 dorsal root ganglia (DRG), no change in L4 DRG, and downregulation in L5 DRG upon spared nerve injury. Genetic ablation of PKG-I specifically in nociceptors or post-treatment with intervertebral foramen injection of PKG-I antagonist, KT5823, attenuated the development and maintenance of spared nerve injury-induced bilateral pain hypersensitivity and anxiety. Mechanistic analysis revealed that activation of PKG-I in nociceptors is responsible for synaptic potentiation in the anterior cingulate cortex upon peripheral neuropathy through presynaptic mechanisms involving brain-derived neurotropic factor signaling. Our results revealed that PKG-I expressed in nociceptors is a key determinant for cingulate synaptic plasticity after nerve injury, which contributes to the maintenance of pain hypersensitivity and anxiety. Thereby, this study presents a strong basis for opening up a novel therapeutic target, PKG-I, in nociceptors for treatment of comorbidity of neuropathic pain and anxiety with least side effects.
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31
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Khakpoor M, Vaseghi S, Mohammadi-Mahdiabadi-Hasani MH, Nasehi M. The effect of GABA-B receptors in the basolateral amygdala on passive avoidance memory impairment induced by MK-801 in rats. Behav Brain Res 2021; 409:113313. [PMID: 33891976 DOI: 10.1016/j.bbr.2021.113313] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 04/17/2021] [Accepted: 04/18/2021] [Indexed: 11/19/2022]
Abstract
MK-801 (dizocilpine) is a potent non-competitive N-methyl-[D]-aspartate (NMDA) receptor antagonist that affects cognitive function, learning, and memory. As we know, NMDA receptors are significantly involved in memory function, as well as GABA (Gamma-Aminobutyric acid) receptors. In this study, we aimed to discover the effect of GABA-B receptors in the basolateral amygdala (BLA) on MK-801-induced memory impairment. We used 160 male Wistar rats. The shuttle box was used to evaluate passive avoidance memory and locomotion apparatus was used to evaluate locomotor activity. MK-801 (0.125, 0.25, and 0.5 μg/rat), baclofen (GABA-B agonist, 0.0001, 0.001, and 0.01 μg/rat) and phaclofen (GABA-B antagonist, 0.0001, 0.001, and 0.01 μg/rat) were injected intra-BLA, after the training. The results showed that MK-801 at the dose of 0.5 μg/rat, baclofen at the doses of 0.001 and 0.01 μg/rat, and phaclofen at the doses of 0.001 and 0.01 μg/rat, impaired passive avoidance memory. Locomotor activity did not alter in all groups. Furthermore, the subthreshold dose of both baclofen (0.0001 μg/rat) and phaclofen (0.0001 μg/rat) restored the impairment effect of MK-801 (0.5 μg/rat) on memory. Also, both baclofen (0.0001 μg/rat) potentiated the impairment effect of MK-801 (0.125 μg/rat) and phaclofen (0.0001 μg/rat) potentiated the impairment effect of MK-801 (0.125 and 0.25 μg/rat) on passive avoidance memory. In conclusion, our results indicated that BLA GABA-B receptors can alter the effect of NMDA inactivation on passive avoidance memory.
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Affiliation(s)
- Mitra Khakpoor
- Department of Basic Science, Farhangian University, Tehran, Iran; Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran
| | - Salar Vaseghi
- Cognitive and Neuroscience Research Center (CNRC), Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran
| | | | - Mohammad Nasehi
- Cognitive and Neuroscience Research Center (CNRC), Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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32
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Deng J, Fang W, Gong Y, Bao Y, Li H, Su S, Sun J, Shi J, Lu L, Shi L, Sun H. Augmentation of fear extinction by theta-burst transcranial magnetic stimulation of the prefrontal cortex in humans. J Psychiatry Neurosci 2021; 46:E292-E302. [PMID: 33844484 PMCID: PMC8061738 DOI: 10.1503/jpn.200053] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Fear extinction alone does not erase the original fear memory. Interventions that enhance extinction can be beneficial for the treatment of fear-related disorders. Repetitive transcranial magnetic stimulation has been shown to improve memory performance. The present study examined the effects of intermittent theta-burst stimulation (iTBS) on fear extinction and the return of fear memory in humans. METHODS Ninety-one young healthy volunteers underwent 3 experiments using a randomized controlled experimental design. Participants first acquired fear conditioning, after which they received 30 Hz iTBS before and after extinction training. The iTBS was applied to 1 of 2 targets: the left dorsolateral prefrontal cortex (dlPFC) and the vertex (control). Fear responses were measured 24 hours later and 1 month later. RESULTS During the spontaneous recovery and reinstatement tests, iTBS of the left dlPFC before and after extinction significantly reduced fear response, whereas iTBS of the vertex had no effect on fear memory performance. This combined approach had a relatively long-lasting effect (i.e., at least 1 month). LIMITATIONS We did not explore the effect of iTBS of the dlPFC on the expression of fear without extinction training. The neural mechanisms of iTBS with fear extinction to inhibit the fear response are unclear. Our results are preliminary and should be interpreted with caution. CONCLUSION `The present results showed that 30 Hz iTBS of the left dlPFC enhanced retention of fear extinction. Our study introduces a new intervention for fear memory and suggests that the left dlPFC may be a treatment target for fear-related disorders.
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Affiliation(s)
- Jiahui Deng
- From the Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Chinese Academy of Medical Sciences Research Unit (No. 2018RU006), Peking University, Beijing 100191, China (Deng, Gong, Li, Su, Sun, Lu, Shi, Sun); the Psychological Hospital Affiliated with Anhui Medical University, Anhui Mental Health Center, Hefei Fourth People's Hospital, Hefei 230022, China (Feng); the National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China (Bao); and the Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100191, China (Lu)
| | - Wenmei Fang
- From the Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Chinese Academy of Medical Sciences Research Unit (No. 2018RU006), Peking University, Beijing 100191, China (Deng, Gong, Li, Su, Sun, Lu, Shi, Sun); the Psychological Hospital Affiliated with Anhui Medical University, Anhui Mental Health Center, Hefei Fourth People's Hospital, Hefei 230022, China (Feng); the National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China (Bao); and the Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100191, China (Lu)
| | - Yimiao Gong
- From the Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Chinese Academy of Medical Sciences Research Unit (No. 2018RU006), Peking University, Beijing 100191, China (Deng, Gong, Li, Su, Sun, Lu, Shi, Sun); the Psychological Hospital Affiliated with Anhui Medical University, Anhui Mental Health Center, Hefei Fourth People's Hospital, Hefei 230022, China (Feng); the National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China (Bao); and the Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100191, China (Lu)
| | - Yanping Bao
- From the Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Chinese Academy of Medical Sciences Research Unit (No. 2018RU006), Peking University, Beijing 100191, China (Deng, Gong, Li, Su, Sun, Lu, Shi, Sun); the Psychological Hospital Affiliated with Anhui Medical University, Anhui Mental Health Center, Hefei Fourth People's Hospital, Hefei 230022, China (Feng); the National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China (Bao); and the Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100191, China (Lu)
| | - Hui Li
- From the Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Chinese Academy of Medical Sciences Research Unit (No. 2018RU006), Peking University, Beijing 100191, China (Deng, Gong, Li, Su, Sun, Lu, Shi, Sun); the Psychological Hospital Affiliated with Anhui Medical University, Anhui Mental Health Center, Hefei Fourth People's Hospital, Hefei 230022, China (Feng); the National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China (Bao); and the Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100191, China (Lu)
| | - Sizhen Su
- From the Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Chinese Academy of Medical Sciences Research Unit (No. 2018RU006), Peking University, Beijing 100191, China (Deng, Gong, Li, Su, Sun, Lu, Shi, Sun); the Psychological Hospital Affiliated with Anhui Medical University, Anhui Mental Health Center, Hefei Fourth People's Hospital, Hefei 230022, China (Feng); the National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China (Bao); and the Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100191, China (Lu)
| | - Jie Sun
- From the Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Chinese Academy of Medical Sciences Research Unit (No. 2018RU006), Peking University, Beijing 100191, China (Deng, Gong, Li, Su, Sun, Lu, Shi, Sun); the Psychological Hospital Affiliated with Anhui Medical University, Anhui Mental Health Center, Hefei Fourth People's Hospital, Hefei 230022, China (Feng); the National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China (Bao); and the Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100191, China (Lu)
| | - Jie Shi
- From the Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Chinese Academy of Medical Sciences Research Unit (No. 2018RU006), Peking University, Beijing 100191, China (Deng, Gong, Li, Su, Sun, Lu, Shi, Sun); the Psychological Hospital Affiliated with Anhui Medical University, Anhui Mental Health Center, Hefei Fourth People's Hospital, Hefei 230022, China (Feng); the National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China (Bao); and the Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100191, China (Lu)
| | - Lin Lu
- From the Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Chinese Academy of Medical Sciences Research Unit (No. 2018RU006), Peking University, Beijing 100191, China (Deng, Gong, Li, Su, Sun, Lu, Shi, Sun); the Psychological Hospital Affiliated with Anhui Medical University, Anhui Mental Health Center, Hefei Fourth People's Hospital, Hefei 230022, China (Feng); the National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China (Bao); and the Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100191, China (Lu)
| | - Le Shi
- From the Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Chinese Academy of Medical Sciences Research Unit (No. 2018RU006), Peking University, Beijing 100191, China (Deng, Gong, Li, Su, Sun, Lu, Shi, Sun); the Psychological Hospital Affiliated with Anhui Medical University, Anhui Mental Health Center, Hefei Fourth People's Hospital, Hefei 230022, China (Feng); the National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China (Bao); and the Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100191, China (Lu)
| | - Hongqiang Sun
- From the Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Chinese Academy of Medical Sciences Research Unit (No. 2018RU006), Peking University, Beijing 100191, China (Deng, Gong, Li, Su, Sun, Lu, Shi, Sun); the Psychological Hospital Affiliated with Anhui Medical University, Anhui Mental Health Center, Hefei Fourth People's Hospital, Hefei 230022, China (Feng); the National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China (Bao); and the Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100191, China (Lu)
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Kuhlmann N, Wagner Valladolid M, Quesada-Ramírez L, Farrer MJ, Milnerwood AJ. Chronic and Acute Manipulation of Cortical Glutamate Transmission Induces Structural and Synaptic Changes in Co-cultured Striatal Neurons. Front Cell Neurosci 2021; 15:569031. [PMID: 33679324 PMCID: PMC7930618 DOI: 10.3389/fncel.2021.569031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 01/26/2021] [Indexed: 12/13/2022] Open
Abstract
In contrast to the prenatal topographic development of sensory cortices, striatal circuit organization is slow and requires the functional maturation of cortical and thalamic excitatory inputs throughout the first postnatal month. While mechanisms regulating synapse development and plasticity are quite well described at excitatory synapses of glutamatergic neurons in the neocortex, comparatively little is known of how this translates to glutamate synapses onto GABAergic neurons in the striatum. Here we investigate excitatory striatal synapse plasticity in an in vitro system, where glutamate can be studied in isolation from dopamine and other neuromodulators. We examined pre-and post-synaptic structural and functional plasticity in GABAergic striatal spiny projection neurons (SPNs), co-cultured with glutamatergic cortical neurons. After synapse formation, medium-term (24 h) TTX silencing increased the density of filopodia, and modestly decreased dendritic spine density, when assayed at 21 days in vitro (DIV). Spine reductions appeared to require residual spontaneous activation of ionotropic glutamate receptors. Conversely, chronic (14 days) TTX silencing markedly reduced spine density without any observed increase in filopodia density. Time-dependent, biphasic changes to the presynaptic marker Synapsin-1 were also observed, independent of residual spontaneous activity. Acute silencing (3 h) did not affect presynaptic markers or postsynaptic structures. To induce rapid, activity-dependent plasticity in striatal neurons, a chemical NMDA receptor-dependent “long-term potentiation (LTP)” paradigm was employed. Within 30 min, this increased spine and GluA1 cluster densities, and the percentage of spines containing GluA1 clusters, without altering the presynaptic signal. The results demonstrate that the growth and pruning of dendritic protrusions is an active process, requiring glutamate receptor activity in striatal projection neurons. Furthermore, NMDA receptor activation is sufficient to drive glutamatergic structural plasticity in SPNs, in the absence of dopamine or other neuromodulators.
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Affiliation(s)
- Naila Kuhlmann
- Centre for Applied Neurogenetics (CAN), University of British Columbia, Vancouver, BC, Canada.,Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
| | | | - Lucía Quesada-Ramírez
- Centre for Applied Neurogenetics (CAN), University of British Columbia, Vancouver, BC, Canada
| | - Matthew J Farrer
- Centre for Applied Neurogenetics (CAN), University of British Columbia, Vancouver, BC, Canada.,McKnight Brain Institute, University of Florida, Gainesville, FL, United States
| | - Austen J Milnerwood
- Centre for Applied Neurogenetics (CAN), University of British Columbia, Vancouver, BC, Canada.,Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
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Korai SA, Ranieri F, Di Lazzaro V, Papa M, Cirillo G. Neurobiological After-Effects of Low Intensity Transcranial Electric Stimulation of the Human Nervous System: From Basic Mechanisms to Metaplasticity. Front Neurol 2021; 12:587771. [PMID: 33658972 PMCID: PMC7917202 DOI: 10.3389/fneur.2021.587771] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 01/04/2021] [Indexed: 12/19/2022] Open
Abstract
Non-invasive low-intensity transcranial electrical stimulation (tES) of the brain is an evolving field that has brought remarkable attention in the past few decades for its ability to directly modulate specific brain functions. Neurobiological after-effects of tES seems to be related to changes in neuronal and synaptic excitability and plasticity, however mechanisms are still far from being elucidated. We aim to review recent results from in vitro and in vivo studies that highlight molecular and cellular mechanisms of transcranial direct (tDCS) and alternating (tACS) current stimulation. Changes in membrane potential and neural synchronization explain the ongoing and short-lasting effects of tES, while changes induced in existing proteins and new protein synthesis is required for long-lasting plastic changes (LTP/LTD). Glial cells, for decades supporting elements, are now considered constitutive part of the synapse and might contribute to the mechanisms of synaptic plasticity. This review brings into focus the neurobiological mechanisms and after-effects of tDCS and tACS from in vitro and in vivo studies, in both animals and humans, highlighting possible pathways for the development of targeted therapeutic applications.
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Affiliation(s)
- Sohaib Ali Korai
- Division of Human Anatomy - Laboratory of Neuronal Networks, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Federico Ranieri
- Neurology Unit, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Vincenzo Di Lazzaro
- Neurology, Neurophysiology and Neurobiology Unit, University Campus Bio-Medico, Rome, Italy
| | - Michele Papa
- Division of Human Anatomy - Laboratory of Neuronal Networks, University of Campania "Luigi Vanvitelli", Naples, Italy.,ISBE Italy, SYSBIO Centre of Systems Biology, Milan, Italy
| | - Giovanni Cirillo
- Division of Human Anatomy - Laboratory of Neuronal Networks, University of Campania "Luigi Vanvitelli", Naples, Italy.,Neurology Unit, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
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Wong HHW, Rannio S, Jones V, Thomazeau A, Sjöström PJ. NMDA receptors in axons: there's no coincidence. J Physiol 2020; 599:367-387. [PMID: 33141440 DOI: 10.1113/jp280059] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 10/27/2020] [Indexed: 12/16/2022] Open
Abstract
In the textbook view, N-methyl-d-aspartate (NMDA) receptors are postsynaptically located detectors of coincident activity in Hebbian learning. However, controversial presynaptically located NMDA receptors (preNMDARs) have for decades been repeatedly reported in the literature. These preNMDARs have typically been implicated in the regulation of short-term and long-term plasticity, but precisely how they signal and what their functional roles are have been poorly understood. The functional roles of preNMDARs across several brain regions and different forms of plasticity can differ vastly, with recent discoveries showing key involvement of unusual subunit composition. Increasing evidence shows preNMDAR can signal through both ionotropic action by fluxing calcium and in metabotropic mode even in the presence of magnesium blockade. We argue that these unusual properties may explain why controversy has surrounded this receptor type. In addition, the expression of preNMDARs at some synapse types but not others can underlie synapse-type-specific plasticity. Last but not least, preNMDARs are emerging therapeutic targets in disease states such as neuropathic pain. We conclude that axonally located preNMDARs are required for specific purposes and do not end up there by accident.
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Affiliation(s)
- Hovy Ho-Wai Wong
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada
| | - Sabine Rannio
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada.,Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
| | - Victoria Jones
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada.,Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
| | - Aurore Thomazeau
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada
| | - P Jesper Sjöström
- Department of Medicine, Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada
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Hadjas LC, Schartner MM, Cand J, Creed MC, Pascoli V, Lüscher C, Simmler LD. Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice. Neuropsychopharmacology 2020; 45:2020-2029. [PMID: 32585679 PMCID: PMC7547074 DOI: 10.1038/s41386-020-0747-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 06/08/2020] [Accepted: 06/09/2020] [Indexed: 11/09/2022]
Abstract
Obsessive-compulsive disorder (OCD) is a circuit disorder involving corticostriatal projections, which play a role in motor control. The Sapap3-knockout (KO) mouse is a mouse model to study OCD and recapitulates OCD-like compulsion through excessive grooming behavior, with skin lesions appearing at advanced age. Deficits in corticostriatal control provide a link to the pathophysiology of OCD. However, there remain significant gaps in the characterization of the Sapap3-KO mouse, with respect to age, specificity of synaptic dysfunction, and locomotor phenotype. We therefore investigated the corticostriatal synaptic phenotype of Sapap3-KO mice using patch-clamp slice electrophysiology, in adult mice and with projection specificity. We also analyzed grooming across age and locomotor phenotype with a novel, unsupervised machine learning technique (MoSeq). Increased grooming in Sapap3-KO mice without skin lesions was age independent. Synaptic deficits persisted in adulthood and involved the projections from the motor cortices and cingulate cortex to the dorsolateral and dorsomedial striatum. Decreased synaptic strength was evident at the input from the primary motor cortex by reduction in AMPA receptor function. Hypolocomotion, i.e., slowness of movement, was consistently observed in Sapap3-KO mice. Our findings emphasize the utility of young adult Sapap3-KO mice to investigate corticostriatal synaptic dysfunction in motor control.
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Affiliation(s)
- Lotfi C. Hadjas
- grid.8591.50000 0001 2322 4988Department of Basic Neurosciences, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland
| | - Michael M. Schartner
- grid.8591.50000 0001 2322 4988Department of Basic Neurosciences, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland
| | - Jennifer Cand
- grid.8591.50000 0001 2322 4988Department of Basic Neurosciences, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland
| | - Meaghan C. Creed
- grid.8591.50000 0001 2322 4988Department of Basic Neurosciences, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland
| | - Vincent Pascoli
- grid.8591.50000 0001 2322 4988Department of Basic Neurosciences, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland
| | - Christian Lüscher
- grid.8591.50000 0001 2322 4988Department of Basic Neurosciences, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland ,grid.150338.c0000 0001 0721 9812Service de Neurologie, Department of Clinical Neurosciences, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland
| | - Linda D. Simmler
- grid.8591.50000 0001 2322 4988Department of Basic Neurosciences, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland
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Fabbrin SB, Girardi BA, de Lorena Wendel A, Coelho Ilha Valin C, Pillat MM, Viero FT, Mello CF, Rubin MA. Spermidine-induced improvement of memory consolidation involves PI3K/Akt signaling pathway. Brain Res Bull 2020; 164:208-213. [PMID: 32858125 DOI: 10.1016/j.brainresbull.2020.08.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 08/18/2020] [Accepted: 08/19/2020] [Indexed: 01/23/2023]
Abstract
Spermidine (SPD) is an endogenous polyamine that plays a facilitatory role in memory acquisition and consolidation. Memory consolidation occurs immediately after learning and again around 3-6 hours later. Current evidence indicates that the polyamine binding site at the NMDA receptor (NMDAr) mediates the effects of SPD on memory. While NMDAr activation increases brain-derived neurotrophic factor (BDNF) release, no study has investigated whether BDNF-activated signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)/Akt pathway play a role in SPD-induced improvement of memory consolidation. Therefore, the aim of the current study was to evaluate whether the TrkB receptor and the PI3K/Akt pathway are involved in the facilitatory effect of SPD on memory consolidation. Male Wistar rats were trained in the contextual conditioned fear task. SPD, ANA-12 (TrkB antagonist), and LY294002 (PI3K inhibitor) were administered immediately after training. The animals were tested 24 h after training. We found that SPD improved fear memory consolidation and that both ANA-12 and LY294002 prevented the facilitatory effect of SPD on memory. These results suggest that SPD-induced improvement of memory consolidation involves the activation of the TrkB receptor and PI3K/Akt pathway.
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Affiliation(s)
- Shaiana Beck Fabbrin
- Graduate Program in Biological Sciences: Toxicological Biochemistry, Center of Exact and Natural Sciences, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil
| | - Bruna Amanda Girardi
- Graduate Program in Biological Sciences: Toxicological Biochemistry, Center of Exact and Natural Sciences, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil
| | - Arithane de Lorena Wendel
- School of Pharmacy, Center of Health Sciences, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil
| | - Carolina Coelho Ilha Valin
- School of Pharmacy, Center of Health Sciences, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil
| | - Micheli Mainardi Pillat
- Graduate Program in Pharmacology, Center of Health Sciences, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil
| | - Fernanda Tibolla Viero
- Graduate Program in Pharmacology, Center of Health Sciences, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil
| | - Carlos Fernando Mello
- Graduate Program in Pharmacology, Center of Health Sciences, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil.
| | - Maribel Antonello Rubin
- Graduate Program in Biological Sciences: Toxicological Biochemistry, Center of Exact and Natural Sciences, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil; Graduate Program in Pharmacology, Center of Health Sciences, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil.
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Induction of BDNF Expression in Layer II/III and Layer V Neurons of the Motor Cortex Is Essential for Motor Learning. J Neurosci 2020; 40:6289-6308. [PMID: 32651187 PMCID: PMC7424868 DOI: 10.1523/jneurosci.0288-20.2020] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 06/09/2020] [Accepted: 06/25/2020] [Indexed: 12/16/2022] Open
Abstract
Motor learning depends on synaptic plasticity between corticostriatal projections and striatal medium spiny neurons. Retrograde tracing from the dorsolateral striatum reveals that both layer II/III and V neurons in the motor cortex express BDNF as a potential regulator of plasticity in corticostriatal projections in male and female mice. The number of these BDNF-expressing cortical neurons and levels of BDNF protein are highest in juvenile mice when adult motor patterns are shaped, while BDNF levels in the adult are low. When mice are trained by physical exercise in the adult, BDNF expression in motor cortex is reinduced, especially in layer II/III projection neurons. Reduced expression of cortical BDNF in 3-month-old mice results in impaired motor learning while space memory is preserved. These findings suggest that activity regulates BDNF expression differentially in layers II/III and V striatal afferents from motor cortex and that cortical BDNF is essential for motor learning. SIGNIFICANCE STATEMENT Motor learning in mice depends on corticostriatal BDNF supply, and regulation of BDNF expression during motor learning is highest in corticostriatal projection neurons in cortical layer II/III.
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Taylor CP, Harris EW. Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins. J Pharmacol Exp Ther 2020; 374:161-174. [PMID: 32321743 DOI: 10.1124/jpet.120.266056] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 04/17/2020] [Indexed: 03/08/2025] Open
Abstract
The gabapentinoid drugs gabapentin and pregabalin (Neurontin and Lyrica) are mainstay treatments for neuropathic pain and preventing focal seizures. Both drugs have similar effects to each other in animal models and clinically. Studies have shown that a protein first identified as an auxiliary subunit of voltage-gated calcium channels (the α 2 δ-subunit type 1 [α 2 δ-1], or Ca V a2d1) is the high-affinity binding site for gabapentin and pregabalin and is required for the efficacy of these drugs. The α 2 δ-1 protein is required for the ability of gabapentin and pregabalin to reduce neurotransmitter release in neuronal tissue, consistent with a therapeutic mechanism of action via voltage-gated calcium channels. However, recent studies have revealed that α 2 δ-1 interacts with several proteins in addition to voltage-gated calcium channels, and these additional proteins could be involved in gabapentinoid pharmacology. Furthermore, gabapentin and pregabalin have been shown to modify the action of a subset of N-methyl-d-aspartate-sensitive glutamate receptors, neurexin-1α, and thrombospondin proteins by binding to α 2 δ-1. Thus, these effects may contribute substantially to gabapentinoid therapeutic mechanism of action. SIGNIFICANCE STATEMENT: It is widely believed that gabapentin and pregabalin act by modestly reducing the membrane localization and activation of voltage-gated calcium channels at synaptic endings in spinal cord and neocortex via binding to the α 2 δ-1 protein. However, recent findings show that the α 2 δ-1 protein also interacts with N-methyl-d-aspartate-sensitive glutamate receptors, neurexin-1α, thrombospondins (adhesion molecules), and other presynaptic proteins. These newly discovered interactions, in addition to actions at calcium channels, may be important mediators of gabapentin and pregabalin therapeutic effects.
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Affiliation(s)
- Charles P Taylor
- CP Taylor Consulting, Chelsea, Michigan (C.P.T.) and Cambrium Group, Raleigh, North Carolina (E.W.H.)
| | - Eric W Harris
- CP Taylor Consulting, Chelsea, Michigan (C.P.T.) and Cambrium Group, Raleigh, North Carolina (E.W.H.)
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Wu Y, Deng F, Wang J, Liu Y, Zhou W, Qu L, Cheng M. Intensity-dependent effects of consecutive treadmill exercise on spatial learning and memory through the p-CREB/BDNF/NMDAR signaling in hippocampus. Behav Brain Res 2020; 386:112599. [PMID: 32184158 DOI: 10.1016/j.bbr.2020.112599] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 03/06/2020] [Accepted: 03/10/2020] [Indexed: 12/23/2022]
Abstract
Exercise is the most recommended non-pharmacological intervention to improve neurocognitive functions under physiological and pathological conditions. However, it remains to be elucidated concerning the influence and the underlying neurological molecular mechanism of different exercise intensity on cognitive function. In this study, we aimed to explore the effects of exercise intensity on spatial learning and memory, as well as the regulation of brain-derived neurotrophic factor (BDNF)/p-CREB/NMDAR signal. In the research, low-intensity consecutive treadmill (LICT) and high-intensity consecutive treadmill (HICT) were implied to rats for 8 weeks. We found that the performances in the Morris water maze were improved in the LICT group, while reduced in the HICT group as compared with the sedentary rats. Moreover, the expression of BDNF mRNA, phosphorylation cAMP-response-element binding protein (p-CREB), mature BDNF (mBDNF), tropomyosin receptor kinase B (TrkB), tissue plasminogen activator (t-PA), and NR2B proteins was increased, whereas the expression of precursor BDNF (proBDNF) and pan-neurotrophin receptor 75 (p75NTR) proteins was decreased in the hippocampus of LICT group compared with the sedentary rats. On the contrary, the expression of proteins and mRNA aforementioned in the LICT group showed a reversed tendency in the hippocampus of HICT rats. These findings suggest that the consecutive low-intensity exercise and high-intensity exercise exert different effects on spatial learning and memory by oppositely regulating the mutual stimulation of p-CREB and BDNF mRNA feedback loop, as well as the t-PA/BDNF/NMDAR which is the post-translation cascades of BDNF signaling.
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Affiliation(s)
- Yulong Wu
- College of Basic Medicine, Binzhou Medical University, Guanhai Road 346, 264003 Yantai, China
| | - Fangfang Deng
- Institute of Health and Disease Management, Binzhou Medical University, Guanhai Road 346, 264003 Yantai, China
| | - Jian Wang
- Affiliated Hospital of Binzhou Medical University, Huanghe Road 661, 256603 Binzhou, China
| | - Yaping Liu
- Institute of Health and Disease Management, Binzhou Medical University, Guanhai Road 346, 264003 Yantai, China
| | - Wei Zhou
- Institute of Health and Disease Management, Binzhou Medical University, Guanhai Road 346, 264003 Yantai, China
| | - Lei Qu
- College of Basic Medicine, Binzhou Medical University, Guanhai Road 346, 264003 Yantai, China
| | - Mei Cheng
- Institute of Health and Disease Management, Binzhou Medical University, Guanhai Road 346, 264003 Yantai, China.
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Calcineurin Inhibition Causes α2δ-1-Mediated Tonic Activation of Synaptic NMDA Receptors and Pain Hypersensitivity. J Neurosci 2020; 40:3707-3719. [PMID: 32269108 DOI: 10.1523/jneurosci.0282-20.2020] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 03/16/2020] [Accepted: 03/22/2020] [Indexed: 12/12/2022] Open
Abstract
Calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, are widely used as standard immunosuppressants in organ transplantation recipients. However, these drugs can cause severe pain in patients, commonly referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin inhibition increases NMDAR activity in the spinal cord, the underlying mechanism remains enigmatic. Using an animal model of CIPS, we found that systemic administration of FK506 in male and female mice significantly increased the amount of α2δ-1-GluN1 complexes in the spinal cord and the level of α2δ-1-bound GluN1 proteins in spinal synaptosomes. Treatment with FK506 significantly increased the frequency of mEPSCs and the amplitudes of monosynaptic EPSCs evoked from the dorsal root and puff NMDAR currents in spinal dorsal horn neurons. Inhibiting α2δ-1 with gabapentin or disrupting the α2δ-1-NMDAR interaction with α2δ-1Tat peptide completely reversed the effects of FK506. In α2δ-1 gene KO mice, treatment with FK506 failed to increase the frequency of NMDAR-mediated mEPSCs and the amplitudes of evoked EPSCs and puff NMDAR currents in spinal dorsal horn neurons. Furthermore, systemic administration of gabapentin or intrathecal injection of α2δ-1Tat peptide reversed thermal and mechanical hypersensitivity in FK506-treated mice. In addition, genetically deleting GluN1 in dorsal root ganglion neurons or α2δ-1 genetic KO similarly attenuated FK506-induced thermal and mechanical hypersensitivity. Together, our findings indicate that α2δ-1-bound NMDARs mediate calcineurin inhibitor-induced tonic activation of presynaptic and postsynaptic NMDARs at the spinal cord level and that presynaptic NMDARs play a prominent role in the development of CIPS.SIGNIFICANCE STATEMENT Calcineurin inhibitors are immunosuppressants used to prevent rejection of transplanted organs and tissues. However, these drugs can cause severe, unexplained pain. We showed that calcineurin inhibition enhances physical interaction between α2δ-1 and NMDARs and their synaptic trafficking in the spinal cord. α2δ-1 is essential for calcineurin inhibitor-induced aberrant activation of presynaptic and postsynaptic NMDARs in the spinal cord. Furthermore, inhibiting α2δ-1 or disrupting α2δ-1-NMDAR interaction reduces calcineurin inhibitor-induced pain hypersensitivity. Eliminating NMDARs in primary sensory neurons or α2δ-1 KO also attenuates calcineurin inhibitor-induced pain hypersensitivity. This new information extends our mechanistic understanding of the role of endogenous calcineurin in regulating synaptic plasticity and nociceptive transmission and suggests new strategies for treating this painful condition.
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Miningou N, Blackwell KT. The road to ERK activation: Do neurons take alternate routes? Cell Signal 2020; 68:109541. [PMID: 31945453 PMCID: PMC7127974 DOI: 10.1016/j.cellsig.2020.109541] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 01/11/2020] [Accepted: 01/12/2020] [Indexed: 01/29/2023]
Abstract
The ERK cascade is a central signaling pathway that regulates a wide variety of cellular processes including proliferation, differentiation, learning and memory, development, and synaptic plasticity. A wide range of inputs travel from the membrane through different signaling pathway routes to reach activation of one set of output kinases, ERK1&2. The classical ERK activation pathway beings with growth factor activation of receptor tyrosine kinases. Numerous G-protein coupled receptors and ionotropic receptors also lead to ERK through increases in the second messengers calcium and cAMP. Though both types of pathways are present in diverse cell types, a key difference is that most stimuli to neurons, e.g. synaptic inputs, are transient, on the order of milliseconds to seconds, whereas many stimuli acting on non-neural tissue, e.g. growth factors, are longer duration. The ability to consolidate these inputs to regulate the activation of ERK in response to diverse signals raises the question of which factors influence the difference in ERK activation pathways. This review presents both experimental studies and computational models aimed at understanding the control of ERK activation and whether there are fundamental differences between neurons and other cells. Our main conclusion is that differences between cell types are quite subtle, often related to differences in expression pattern and quantity of some molecules such as Raf isoforms. In addition, the spatial location of ERK is critical, with regulation by scaffolding proteins producing differences due to colocalization of upstream molecules that may differ between neurons and other cells.
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Affiliation(s)
- Nadiatou Miningou
- Department of Chemistry and Biochemistry, George Mason University, Fairfax, VA 22030, United States of America
| | - Kim T Blackwell
- Interdisciplinary Program in Neuroscience and Bioengineering Department, George Mason University, Fairfax, VA 22030, United States of America.
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Kim Y, Jang YN, Kim JY, Kim N, Noh S, Kim H, Queenan BN, Bellmore R, Mun JY, Park H, Rah JC, Pak DTS, Lee KJ. Microtubule-associated protein 2 mediates induction of long-term potentiation in hippocampal neurons. FASEB J 2020; 34:6965-6983. [PMID: 32237183 DOI: 10.1096/fj.201902122rr] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 03/16/2020] [Accepted: 03/17/2020] [Indexed: 12/19/2022]
Abstract
Microtubule-associated protein (MAP) 2 has been perceived as a static cytoskeletal protein enriched in neuronal dendritic shafts. Emerging evidence indicates dynamic functions for various MAPs in activity-dependent synaptic plasticity. However, it is unclear how MAP2 is associated with synaptic plasticity mechanisms. Here, we demonstrate that specific silencing of high-molecular-weight MAP2 in vivo abolished induction of long-term potentiation (LTP) in the Schaffer collateral pathway of CA1 pyramidal neurons and in vitro blocked LTP-induced surface delivery of AMPA receptors and spine enlargement. In mature hippocampal neurons, we observed rapid translocation of a subpopulation of MAP2, present in dendritic shafts, to spines following LTP stimulation. Time-lapse confocal imaging showed that spine translocation of MAP2 was coupled with LTP-induced spine enlargement. Consistently, immunogold electron microscopy revealed that LTP stimulation of the Schaffer collateral pathway promoted MAP2 labeling in spine heads of CA1 neurons. This translocation depended on NMDA receptor activation and Ras-MAPK signaling. Furthermore, LTP stimulation led to an increase in surface-expressed AMPA receptors specifically in the neurons with MAP2 spine translocation. Altogether, this study indicates a novel role for MAP2 in LTP mechanisms and suggests that MAP2 participates in activity-dependent synaptic plasticity in mature hippocampal networks.
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Affiliation(s)
- Yoonju Kim
- Neural Circuits Research Group, Korea Basic Science Research Institute (KBRI), Daegu, Republic of Korea
| | - You-Na Jang
- Neural Circuits Research Group, Korea Basic Science Research Institute (KBRI), Daegu, Republic of Korea
| | - Ji-Young Kim
- Neurovascular Unit Research Group, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea
| | - Nari Kim
- Center for Cortical Processing, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea
| | - Seulgi Noh
- Neural Circuits Research Group, Korea Basic Science Research Institute (KBRI), Daegu, Republic of Korea
| | - Hyeyeon Kim
- Neurovascular Unit Research Group, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea
| | - Bridget N Queenan
- Department of Pharmacology and Physiology, Interdisciplinary Program of Neuroscience, Georgetown University Medical Center, Washington, DC, USA
| | - Ryan Bellmore
- Department of Pharmacology and Physiology, Interdisciplinary Program of Neuroscience, Georgetown University Medical Center, Washington, DC, USA
| | - Ji Young Mun
- Neural Circuits Research Group, Korea Basic Science Research Institute (KBRI), Daegu, Republic of Korea
| | - Hyungju Park
- Neurovascular Unit Research Group, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea.,Department of Brain and Cognitive Sciences, DGIST, Daegu, Republic of Korea
| | - Jong Cheol Rah
- Center for Cortical Processing, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea.,Department of Brain and Cognitive Sciences, DGIST, Daegu, Republic of Korea
| | - Daniel T S Pak
- Department of Pharmacology and Physiology, Interdisciplinary Program of Neuroscience, Georgetown University Medical Center, Washington, DC, USA
| | - Kea Joo Lee
- Neural Circuits Research Group, Korea Basic Science Research Institute (KBRI), Daegu, Republic of Korea.,Center for Cortical Processing, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea.,Department of Brain and Cognitive Sciences, DGIST, Daegu, Republic of Korea
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Cole RD, Zimmerman M, Matchanova A, Kutlu MG, Gould TJ, Parikh V. Cognitive rigidity and BDNF-mediated frontostriatal glutamate neuroadaptations during spontaneous nicotine withdrawal. Neuropsychopharmacology 2020; 45:866-876. [PMID: 31752015 PMCID: PMC7075915 DOI: 10.1038/s41386-019-0574-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 10/13/2019] [Accepted: 11/14/2019] [Indexed: 01/12/2023]
Abstract
Cognitive flexibility is the ability to switch strategic responses adaptively in changing environments. Cognitive rigidity imposed by neural circuit adaptations during nicotine abstinence may foster maladaptive nicotine taking in addicts. We systematically examined the effects of spontaneous withdrawal in mice exposed to either nicotine (6.3 or 18 mg/kg/day) or saline for 14 days on cognitive flexibility using an operant strategy set-shifting task. Because frontostriatal circuits are critical for cognitive flexibility and brain-derived neurotrophic factor (BDNF) modulates glutamate plasticity in these circuits, we also explored the effects of nicotine withdrawal on these neurochemical substrates. Mice undergoing nicotine withdrawal required more trials to attain strategy-switching criterion. Error analysis show that animals withdrawn from both nicotine doses committed higher perseverative errors, which correlated with measures of anxiety. However, animals treated with the higher nicotine dose also displayed more strategy maintenance errors that remained independent of negative affect. BDNF mRNA expression increased in the medial prefrontal cortex (mPFC) following nicotine withdrawal. Surprisingly, BDNF protein declined in mPFC but was elevated in dorsal striatum (DS). DS BDNF protein positively correlated with perseverative and maintenance errors, suggesting mPFC-DS overflow of BDNF during withdrawal. BDNF-evoked glutamate release and synapsin phosphorylation was attenuated within DS synapses, but enhanced in the nucleus accumbens, suggesting a dichotomous role of BDNF signaling in striatal regions. Taken together, these data suggest that spontaneous nicotine withdrawal impairs distinct components of cognitive set-shifting and these deficits may be linked to BDNF-mediated alterations in glutamate signaling dynamics in discrete frontostriatal circuits.
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Affiliation(s)
- Robert D. Cole
- 0000 0001 2248 3398grid.264727.2Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA 19122 USA
| | - Matty Zimmerman
- 0000 0001 2248 3398grid.264727.2Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA 19122 USA
| | - Anastasia Matchanova
- 0000 0001 2248 3398grid.264727.2Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA 19122 USA
| | - Munir Gunes Kutlu
- 0000 0001 2097 4281grid.29857.31Department of Biobehavioral Health, Pennsylvania State University, University Park, PA 16802 USA
| | - Thomas J. Gould
- 0000 0001 2097 4281grid.29857.31Department of Biobehavioral Health, Pennsylvania State University, University Park, PA 16802 USA
| | - Vinay Parikh
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA, 19122, USA.
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45
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Hoirisch-Clapauch S, Nardi AE. Antidepressants: bleeding or thrombosis? Thromb Res 2020; 181 Suppl 1:S23-S28. [PMID: 31477223 DOI: 10.1016/s0049-3848(19)30362-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 03/10/2019] [Accepted: 05/03/2019] [Indexed: 02/02/2023]
Abstract
The contribution of depression to the pathogenesis of cardiovascular disease includes autonomic disturbances, endothelial dysfunction, inflammation, smoking, sedentary lifestyle, carbohydrate craving, and impaired fibrinolysis. There is evidence that serotonergic antidepressants (selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors) restore the fibrinolytic profile. Contrary to common belief, such antidepressants do not affect platelet aggregation induced by adenosine diphosphate or adrenaline but reduce platelet adhesion to collagen. Since platelet collagen receptor glycoprotein VI binds to fibrin, it is possible that fibrinolytic properties of serotonergic antidepressants could impair platelet adhesion to collagen. The profibrinolytic and antiplatelet properties of serotonergic antidepressants help explain the increased risk of gastrointestinal, intracranial, and surgical bleeding in patients using these medications. Studies evaluating the impact of antidepressants on thrombotic and cardiovascular risk have yielded contradictory results. Corroborating the hypothesis that serotonergic antidepressants have profibrinolytic and antiplatelet properties, some authors showed that these medications prevent both cardiovascular and thromboembolic events. Others showed an increased risk of ischemic stroke, cardiac events and thromboembolic disease. Silent brain infarction may present in some elders with depressive symptoms, so it is presumed that antidepressants are prescribed for subclinical stroke patients. Another explanation for the increased risk of cardiovascular and thromboembolic events reported by some authors in individuals taking antidepressants includes antidepressant side effects such as sedation and weight gain and depression comorbidities such as anxiety, obesity and hyperhomocysteinemia. In conclusion, we suggest that serotonergic antidepressants be considered weak anticoagulants. We also suggest that depressed patients with comorbidities increasing the risk of cardiovascular and thromboembolic disease be recommended to follow a balanced diet and engage in physical activity, such as daily walking.
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Affiliation(s)
| | - Antonio E Nardi
- Institute of Psychiatry, Federal University of Rio de Janeiro, Brazil
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46
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Ronzano R, Thetiot M, Lubetzki C, Desmazieres A. Myelin Plasticity and Repair: Neuro-Glial Choir Sets the Tuning. Front Cell Neurosci 2020; 14:42. [PMID: 32180708 PMCID: PMC7059744 DOI: 10.3389/fncel.2020.00042] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 02/12/2020] [Indexed: 12/11/2022] Open
Abstract
The plasticity of the central nervous system (CNS) in response to neuronal activity has been suggested as early as 1894 by Cajal (1894). CNS plasticity has first been studied with a focus on neuronal structures. However, in the last decade, myelin plasticity has been unraveled as an adaptive mechanism of importance, in addition to the previously described processes of myelin repair. Indeed, it is now clear that myelin remodeling occurs along with life and adapts to the activity of neuronal networks. Until now, it has been considered as a two-part dialog between the neuron and the oligodendroglial lineage. However, other glial cell types might be at play in myelin plasticity. In the present review, we first summarize the key structural parameters for myelination, we then describe how neuronal activity modulates myelination and finally discuss how other glial cells could participate in myelinic adaptivity.
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Affiliation(s)
- Remi Ronzano
- Institut du Cerveau et de la Moelle épinière, Sorbonne Universités UPMC Université Paris 06, CNRS UMR7225-Inserm U1127, Paris, France
| | - Melina Thetiot
- Institut du Cerveau et de la Moelle épinière, Sorbonne Universités UPMC Université Paris 06, CNRS UMR7225-Inserm U1127, Paris, France
- Unit Zebrafish Neurogenetics, Department of Developmental & Stem Cell Biology, Institut Pasteur, CNRS, Paris, France
| | - Catherine Lubetzki
- Institut du Cerveau et de la Moelle épinière, Sorbonne Universités UPMC Université Paris 06, CNRS UMR7225-Inserm U1127, Paris, France
- Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France
| | - Anne Desmazieres
- Institut du Cerveau et de la Moelle épinière, Sorbonne Universités UPMC Université Paris 06, CNRS UMR7225-Inserm U1127, Paris, France
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Tomás FJB, Turko P, Heilmann H, Trimbuch T, Yanagawa Y, Vida I, Münster-Wandowski A. BDNF Expression in Cortical GABAergic Interneurons. Int J Mol Sci 2020; 21:E1567. [PMID: 32106593 PMCID: PMC7084226 DOI: 10.3390/ijms21051567] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 02/07/2020] [Accepted: 02/21/2020] [Indexed: 12/14/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is a major neuronal growth factor that is widely expressed in the central nervous system. It is synthesized as a glycosylated precursor protein, (pro)BDNF and post-translationally converted to the mature form, (m)BDNF. BDNF is known to be produced and secreted by cortical glutamatergic principal cells (PCs); however, it remains a question whether it can also be synthesized by other neuron types, in particular, GABAergic interneurons (INs). Therefore, we utilized immunocytochemical labeling and reverse transcription quantitative PCR (RT-qPCR) to investigate the cellular distribution of proBDNF and its RNA in glutamatergic and GABAergic neurons of the mouse cortex. Immunofluorescence labeling revealed that mBDNF, as well as proBDNF, localized to both the neuronal populations in the hippocampus. The precursor proBDNF protein showed a perinuclear distribution pattern, overlapping with the rough endoplasmic reticulum (ER), the site of protein synthesis. RT-qPCR of samples obtained using laser capture microdissection (LCM) or fluorescence-activated cell sorting (FACS) of hippocampal and cortical neurons further demonstrated the abundance of BDNF transcripts in both glutamatergic and GABAergic cells. Thus, our data provide compelling evidence that BDNF can be synthesized by both principal cells and INs of the cortex.
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Affiliation(s)
- Federico José Barreda Tomás
- Institute of Integrative Neuroanatomy, Charité-Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany; (F.J.B.T.); (P.T.); (H.H.); (I.V.)
- Bernstein Center for Computational Neuroscience (BCCN) Berlin, 10115 Berlin, Germany
| | - Paul Turko
- Institute of Integrative Neuroanatomy, Charité-Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany; (F.J.B.T.); (P.T.); (H.H.); (I.V.)
| | - Heike Heilmann
- Institute of Integrative Neuroanatomy, Charité-Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany; (F.J.B.T.); (P.T.); (H.H.); (I.V.)
| | - Thorsten Trimbuch
- Institute of Neurophysiology, Charité - Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany;
| | - Yuchio Yanagawa
- Departments of Genetic and Behavioral Neuroscience, Graduate School of Medicine, Gunma University, Graduate School of Medicine, Maebashi City 371-8511, Japan;
| | - Imre Vida
- Institute of Integrative Neuroanatomy, Charité-Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany; (F.J.B.T.); (P.T.); (H.H.); (I.V.)
- Bernstein Center for Computational Neuroscience (BCCN) Berlin, 10115 Berlin, Germany
| | - Agnieszka Münster-Wandowski
- Institute of Integrative Neuroanatomy, Charité-Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany; (F.J.B.T.); (P.T.); (H.H.); (I.V.)
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Ito W, Fusco B, Morozov A. Disinhibition-assisted long-term potentiation in the prefrontal-amygdala pathway via suppression of somatostatin-expressing interneurons. NEUROPHOTONICS 2020; 7:015007. [PMID: 32090134 PMCID: PMC7019182 DOI: 10.1117/1.nph.7.1.015007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 01/27/2020] [Indexed: 06/10/2023]
Abstract
Significance: Natural brain adaptations often involve changes in synaptic strength. The artificial manipulations can help investigate the role of synaptic strength in a specific brain circuit not only in various physiological phenomena like correlated neuronal firing and oscillations but also in behaviors. High- and low-frequency stimulation at presynaptic sites has been used widely to induce long-term potentiation (LTP) and depression. This approach is effective in many brain areas but not in the basolateral amygdala (BLA) because the robust local GABAergic tone inside BLA restricts synaptic plasticity. Aim: We aimed at identifying the subclass of GABAergic neurons that gate LTP in the BLA afferents from the dorsomedial prefrontal cortex (dmPFC). Approach: Chemogenetic or optogenetic suppression of specific GABAergic neurons in BLA was combined with high-frequency stimulation of the BLA afferents as a method for LTP induction. Results: Chemogenetic suppression of somatostatin-positive interneurons (Sst-INs) enabled the ex vivo LTP by high-frequency stimulation of the afferent but the suppression of parvalbumin-positive interneurons (PV-INs) did not. Moreover, optogenetic suppression of Sst-INs with Arch also enabled LTP of the dmPFC-BLA synapses, both ex vivo and in vivo. Conclusions: These findings reveal that Sst-INs but not PV-INs gate LTP in the dmPFC-BLA pathway and provide a method for artificial synaptic facilitation in BLA.
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Affiliation(s)
- Wataru Ito
- Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, United States
| | - Brendon Fusco
- Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, United States
| | - Alexei Morozov
- Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, United States
- Virginia Tech, School of Biomedical Engineering and Sciences, Blacksburg, Virginia, United States
- Virginia Tech Carilion School of Medicine, Department of Psychiatry and Behavioral Medicine, Roanoke, Virginia, United States
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Differences in GluN2B-Containing NMDA Receptors Result in Distinct Long-Term Plasticity at Ipsilateral versus Contralateral Cortico-Striatal Synapses. eNeuro 2019; 6:ENEURO.0118-19.2019. [PMID: 31744842 PMCID: PMC6883172 DOI: 10.1523/eneuro.0118-19.2019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 10/14/2019] [Accepted: 11/06/2019] [Indexed: 12/24/2022] Open
Abstract
Excitatory neurons in the primary motor cortex project bilaterally to the striatum. However, whether synaptic structure and function in ipsilateral and contralateral cortico-striatal pathways is identical or different remains largely unknown. Here, we describe that excitatory synapses in the mouse contralateral pathway have higher levels of NMDA-type of glutamate receptors (NMDARs) than those in the ipsilateral pathway, although both synapses utilize the same presynaptic vesicular glutamate transporter (VGLUT). We also show that NMDARs containing the GluN2B subunit, but not GluN2A, contribute to this difference. The altered NMDAR subunit composition in these two pathways results in opposite synaptic plasticity induced by θ-burst stimulus: long-term depression in the ipsilateral pathway and long-term potentiation (LTP) in the contralateral pathway. The standard long-term depression (LTD)-inducing protocol using paired postsynaptic and presynaptic activity triggers synaptic depression at ipsilateral pathway synapses, but not at those of the contralateral pathway. Altogether, our results provide novel and unexpected evidence for the lack of bilaterality of NMDAR-mediated synaptic transmission at cortico-striatal pathways due to differences in the expression of GluN2B subunits, which results in differences in bidirectional synaptic plasticity.
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50
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Li W, Pozzo-Miller L. Dysfunction of the corticostriatal pathway in autism spectrum disorders. J Neurosci Res 2019; 98:2130-2147. [PMID: 31758607 DOI: 10.1002/jnr.24560] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 11/04/2019] [Accepted: 11/05/2019] [Indexed: 12/14/2022]
Abstract
The corticostriatal pathway that carries sensory, motor, and limbic information to the striatum plays a critical role in motor control, action selection, and reward. Dysfunction of this pathway is associated with many neurological and psychiatric disorders. Corticostriatal synapses have unique features in their cortical origins and striatal targets. In this review, we first describe axonal growth and synaptogenesis in the corticostriatal pathway during development, and then summarize the current understanding of the molecular bases of synaptic transmission and plasticity at mature corticostriatal synapses. Genes associated with autism spectrum disorder (ASD) have been implicated in axonal growth abnormalities, imbalance of the synaptic excitation/inhibition ratio, and altered long-term synaptic plasticity in the corticostriatal pathway. Here, we review a number of ASD-associated high-confidence genes, including FMR1, KMT2A, GRIN2B, SCN2A, NLGN1, NLGN3, MET, CNTNAP2, FOXP2, TSHZ3, SHANK3, PTEN, CHD8, MECP2, DYRK1A, RELN, FOXP1, SYNGAP1, and NRXN, and discuss their relevance to proper corticostriatal function.
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Affiliation(s)
- Wei Li
- Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lucas Pozzo-Miller
- Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL, USA
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