|
1
|
Cheng W, Wang Y, Sa P, Liang L, Zhang L, Shen G, Luo J, Li M. Transcriptomics and metabolomics reveal the mechanism of cognitive impairment induced by long-term selenium deficiency in mice. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 299:118367. [PMID: 40398250 DOI: 10.1016/j.ecoenv.2025.118367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 03/07/2025] [Accepted: 05/18/2025] [Indexed: 05/23/2025]
Abstract
As the aging population increases, cognitive impairment is emerging as a growing health issue worldwide. Low selenium status has been reported to correlate with cognitive decline in older adults. Nonetheless, the impact of prolonged selenium deficiency on cognitive function in adult mice and the underlying mechanisms remain poorly understood. In this research, male C57BL/6 J mice were given either a normal diet (0.2 mg/kg Se) or a selenium-deficient diet (0.02 mg/kg Se) for 24 weeks to evaluate the impact of long-term selenium insufficiency on their cognitive abilities. We performed hippocampus transcriptome sequencing, real-time PCR, Golgi-Cox staining, transmission electron microscopy, western blotting, and untargeted brain metabolomics to uncover the underlying regulatory mechanism. We found that chronic selenium deficiency impaired the capabilities of object recognition, spatial memory, and self-caring in mice, and disrupted the expression of key genes related to cognitive behavior, dendrite morphogenesis, and synaptic plasticity. Additionally, prolonged selenium deficiency compromised neurite integrity, decreased dendritic spine density, impaired synaptic ultrastructure, and reduced synaptic protein expression. Brain metabolomics revealed that differential metabolites (methylmalonic acid, N-acetyl-1-aspartylglutamic acid, and S-adenosylmethionine) may be involved in the process of cognitive impairment. These findings suggest that perturbation in cognition-related transcriptome profiles, lesions in neurites and synapses, and remodeling of the brain metabolic pattern are involved in the cognitive impairment induced by long-term selenium deficiency. Our study offers a new perspective on the pathogenesis of cognitive impairment, highlighting the critical role of selenium supplementation in maintaining healthy cognitive function.
Collapse
Affiliation(s)
- Wanpeng Cheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou 221004, China; Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou 221004, China
| | - Yani Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou 221004, China; Department of Anatomy, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou 221004, China
| | - Peiyue Sa
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou 221004, China; Department of Anatomy, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou 221004, China
| | - Luyun Liang
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou 221004, China; The First Clinical College of Xuzhou Medical University, Xuzhou 221004, China
| | - Lantian Zhang
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou 221004, China; Department of Anatomy, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou 221004, China
| | - Guangyan Shen
- The First Clinical College of Hainan Medical University, Haikou 571199, China
| | - Jincheng Luo
- Key Laboratory for Gout Research, School of Public Health, Jiamusi University, Jiamusi 154007, China
| | - Mengdi Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou 221004, China; Department of Anatomy, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou 221004, China.
| |
Collapse
|
|
2
|
Kaytanli B, Bacca M. Morphological trapping of neurotransmitters in synaptic clefts: A new dimension in neural plasticity. Biophys J 2025; 124:1035-1037. [PMID: 40023764 PMCID: PMC11993914 DOI: 10.1016/j.bpj.2025.02.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 02/25/2025] [Accepted: 02/27/2025] [Indexed: 03/04/2025] Open
Affiliation(s)
| | - Mattia Bacca
- Mechanical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.
| |
Collapse
|
|
3
|
Mesa MH, McCabe KJ, Rangamani P. Synaptic cleft geometry modulates NMDAR opening probability by tuning neurotransmitter residence time. Biophys J 2025; 124:1058-1072. [PMID: 39876560 PMCID: PMC11993924 DOI: 10.1016/j.bpj.2025.01.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/27/2024] [Accepted: 01/23/2025] [Indexed: 01/30/2025] Open
Abstract
Synaptic morphology plays a critical role in modulating the dynamics of neurotransmitter diffusion and receptor activation in interneuron communication. Central physical aspects of synaptic geometry, such as the curvature of the synaptic cleft, the distance between the presynaptic and postsynaptic membranes, and the surface-area-to-volume ratio of the cleft, crucially influence glutamate diffusion and N-methyl-D-aspartate receptor (NMDAR) opening probabilities. In this study, we developed a stochastic model for receptor activation using realistic synaptic geometries. Our simulations revealed substantial variability in NMDAR activation, showing a significant impact of synaptic structure on receptor activation. Next, we designed a theoretical study with idealized cleft geometries to understand the impact of different biophysical properties on receptor activation. Specifically, we found that increasing the curvature of the synaptic membranes could compensate for reduced NMDAR activation when the synaptic cleft width was large. Additionally, nonparallel membrane configurations, such as convex presynapses or concave postsynaptic densities, maximize NMDAR activation by increasing the surface-area-to-volume ratio, thereby increasing glutamate residence time and reducing glutamate escape. Furthermore, clustering NMDARs within the postsynaptic density significantly increased receptor activation across different geometric conditions and mitigated the effects of synaptic morphology on NMDAR opening probabilities. These findings highlight the complex interplay between synaptic geometry and receptor dynamics and provide important insights into how structural modifications can influence synaptic efficacy and plasticity. By considering the major physical factors that affect neurotransmitter diffusion and receptor activation, our work offers a comprehensive understanding of how variations in synaptic geometry may regulate neurotransmission.
Collapse
Affiliation(s)
- María Hernández Mesa
- Department of Computational Physiology, Simula Research Laboratory, 0164 Oslo, Norway; Department of Informatics, University of Oslo, 0373 Oslo, Norway
| | - Kimberly J McCabe
- Department of Computational Physiology, Simula Research Laboratory, 0164 Oslo, Norway
| | - Padmini Rangamani
- Department of Pharmacology, School of Medicine, University of California, San Diego, San Diego, California; Department of Mechanical and Aerospace Engineering, University of California, San Diego, San Diego, California.
| |
Collapse
|
|
4
|
Mishra S, Stany B, Das A, Kanagavel D, Vijayan M. A Comprehensive Review of Membrane Transporters and MicroRNA Regulation in Alzheimer's Disease. Mol Neurobiol 2024; 61:8739-8758. [PMID: 38558361 DOI: 10.1007/s12035-024-04135-2] [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: 11/22/2023] [Accepted: 03/15/2024] [Indexed: 04/04/2024]
Abstract
Alzheimer's disease (AD) is a distressing neurodegenerative condition characterized by the accumulation of amyloid-beta (Aβ) plaques and tau tangles within the brain. The interconnectedness between membrane transporters (SLCs) and microRNAs (miRNAs) in AD pathogenesis has gained increasing attention. This review explores the localization, substrates, and functions of SLC transporters in the brain, emphasizing the roles of transporters for glutamate, glucose, nucleosides, and other essential compounds. The examination delves into the significance of SLCs in AD, their potential for drug development, and the intricate realm of miRNAs, encompassing their transcription, processing, functions, and regulation. MiRNAs have emerged as significant players in AD, including those associated with mitochondria and synapses. Furthermore, this review discusses the intriguing nexus of miRNAs targeting SLC transporters and their potential as therapeutic targets in AD. Finally, the review underscores the interaction between SLC transporters and miRNA regulation within the context of Alzheimer's disease, underscoring the need for further research in this area. This comprehensive review aims to shed light on the complex mechanisms underlying the causation of AD and provides insights into potential therapeutic approaches.
Collapse
Affiliation(s)
- Shatakshi Mishra
- School of Biosciences and Technology, Department of Biotechnology, VIT University, Vellore, Tamil Nadu, 632014, India
| | - B Stany
- School of Biosciences and Technology, Department of Biotechnology, VIT University, Vellore, Tamil Nadu, 632014, India
| | - Anushka Das
- School of Biosciences and Technology, Department of Biotechnology, VIT University, Vellore, Tamil Nadu, 632014, India
| | - Deepankumar Kanagavel
- School of Biosciences and Technology, Department of Biotechnology, VIT University, Vellore, Tamil Nadu, 632014, India.
| | - Murali Vijayan
- Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX, 79430, USA.
| |
Collapse
|
|
5
|
Naveed K, Rashidi-Ranjbar N, Kumar S, Zomorrodi R, Blumberger DM, Fischer CE, Sanches M, Mulsant BH, Pollock BG, Voineskos AN, Rajji TK. Effect of dorsolateral prefrontal cortex structural measures on neuroplasticity and response to paired-associative stimulation in Alzheimer's dementia. Philos Trans R Soc Lond B Biol Sci 2024; 379:20230233. [PMID: 38853564 PMCID: PMC11343312 DOI: 10.1098/rstb.2023.0233] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 12/04/2023] [Accepted: 01/15/2024] [Indexed: 06/11/2024] Open
Abstract
Long-term potentiation (LTP)-like activity can be induced by stimulation protocols such as paired associative stimulation (PAS). We aimed to determine whether PAS-induced LTP-like activity (PAS-LTP) of the dorsolateral prefrontal cortex (DLPFC) is associated with cortical thickness and other structural measures impaired in Alzheimer's dementia (AD). We also explored longitudinal relationships between these brain structures and PAS-LTP response after a repetitive PAS (rPAS) intervention. Mediation and regression analyses were conducted using data from randomized controlled trials with AD and healthy control participants. PAS-electroencephalography assessed DLPFC PAS-LTP. DLPFC thickness and surface area were acquired from T1-weighted magnetic resonance imaging. Fractional anisotropy and mean diffusivity (MD) of the superior longitudinal fasciculus (SLF)-a tract important to induce PAS-LTP-were measured with diffusion-weighted imaging. AD participants exhibited reduced DLPFC thickness and increased SLF MD. There was also some evidence that reduction in DLPFC thickness mediates DLPFC PAS-LTP impairment. Longitudinal analyses showed preliminary evidence that SLF MD, and to a lesser extent DLPFC thickness, is associated with DLPFC PAS-LTP response to active rPAS. This study expands our understanding of the relationships between brain structural changes and neuroplasticity. It provides promising evidence for a structural predictor to improving neuroplasticity in AD with neurostimulation. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Collapse
Affiliation(s)
- K. Naveed
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Toronto Dementia Research Alliance, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
| | - N. Rashidi-Ranjbar
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Toronto Dementia Research Alliance, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, 209 Victoria Street, Toronto, OntarioM5B 1T8, Canada
| | - S. Kumar
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Toronto Dementia Research Alliance, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
- Campbell Family Mental Health Research Institute, CAMH, 479 Spadina Avenue, Toronto, OntarioM5S 2S1, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
| | - R. Zomorrodi
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Campbell Family Mental Health Research Institute, CAMH, 479 Spadina Avenue, Toronto, OntarioM5S 2S1, Canada
| | - D. M. Blumberger
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Campbell Family Mental Health Research Institute, CAMH, 479 Spadina Avenue, Toronto, OntarioM5S 2S1, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
| | - C. E. Fischer
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Toronto Dementia Research Alliance, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, 209 Victoria Street, Toronto, OntarioM5B 1T8, Canada
| | - M. Sanches
- Biostatistics Core, Centre for Addiction and Mental Health, 60 White Squirrel Way, Toronto, OntarioM6J 1H4, Canada
| | - B. H. Mulsant
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Toronto Dementia Research Alliance, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
- Campbell Family Mental Health Research Institute, CAMH, 479 Spadina Avenue, Toronto, OntarioM5S 2S1, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
| | - B. G. Pollock
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Campbell Family Mental Health Research Institute, CAMH, 479 Spadina Avenue, Toronto, OntarioM5S 2S1, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
| | - A. N. Voineskos
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Campbell Family Mental Health Research Institute, CAMH, 479 Spadina Avenue, Toronto, OntarioM5S 2S1, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
| | - T. K. Rajji
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Toronto Dementia Research Alliance, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
- Campbell Family Mental Health Research Institute, CAMH, 479 Spadina Avenue, Toronto, OntarioM5S 2S1, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
| |
Collapse
|
|
6
|
Deng L, Jiang H, Lin J, Xu D, Qi A, Guo Q, Li PP, Wang X, Liu JS, Fu X, Li P. Clock knockout in inhibitory neurons reduces predisposition to epilepsy and influences anxiety-like behaviors in mice. Neurobiol Dis 2024; 193:106457. [PMID: 38423191 DOI: 10.1016/j.nbd.2024.106457] [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: 10/23/2023] [Revised: 02/21/2024] [Accepted: 02/25/2024] [Indexed: 03/02/2024] Open
Abstract
Epilepsy is a brain disorder affecting up to 1 in 26 individuals. Despite its clinical importance, the molecular mechanisms of epileptogenesis are still far from clarified. Our previous study showed that disruption of Clock in excitatory neurons alters cortical circuits and leads to generation of focal epilepsy. In this study, a GAD-Cre;Clockflox/flox mouse line with conditional Clock gene knockout in inhibitory neurons was established. We observed that seizure latency was prolonged, the severity and mortality of pilocarpine-induced seizure were significantly reduced, and memory was improved in GAD-Cre;Clockflox/flox mice. We hypothesize that mice with CLOCK knockout in inhibitory neurons have increased threshold for seizure, opposite from mice with CLOCK knockout in excitatory neurons. Further investigation showed Clock knockout in inhibitory neurons upregulated the basal protein level of ARC, a synaptic plasticity-associated immediate-early gene product, likely through the BDNF-ERK pathway. Altered basal levels of ARC may play an important role in epileptogenesis after Clock deletion in inhibitory neurons. Although sEPSCs and intrinsic properties of layer 5 pyramidal neurons in the somatosensory cortex exhibit no changes, the spine density increased in apical dendrite of pyramidal neurons in CLOCK knockout group. Our results suggest an underlying mechanism by which the circadian protein CLOCK in inhibitory neurons participates in neuronal activity and regulates the predisposition to epilepsy.
Collapse
Affiliation(s)
- Lu Deng
- Department of Geriatrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Hong Jiang
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Jingjing Lin
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Di Xu
- Department of Geriatrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Ailin Qi
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Qing Guo
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Ping-Ping Li
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Xinshi Wang
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Shangcai Village, Ouhai District, Wenzhou, Zhejiang Province, China
| | - Judy S Liu
- Department of Neurology, Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02903, USA.
| | - Xiaoqin Fu
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
| | - Peijun Li
- Department of Geriatrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China; Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China; Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117, Jinan, Shandong, China.
| |
Collapse
|
|
7
|
Collier TJ, Begg L, Stancati JA, Mercado NM, Sellnow RC, Sandoval IM, Sortwell CE, Steece-Collier K. Quinpirole inhibits levodopa-induced dyskinesias at structural and behavioral levels: Efficacy negated by co-administration of isradipine. Exp Neurol 2023; 369:114522. [PMID: 37640098 PMCID: PMC10591902 DOI: 10.1016/j.expneurol.2023.114522] [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: 04/21/2023] [Revised: 08/06/2023] [Accepted: 08/20/2023] [Indexed: 08/31/2023]
Abstract
Dopamine depletion associated with parkinsonism induces plastic changes in striatal medium spiny neurons (MSN) that are maladaptive and associated with the emergence of the negative side-effect of standard treatment: the abnormal involuntary movements termed levodopa-induced dyskinesia (LID). Prevention of MSN dendritic spine loss is hypothesized to diminish liability for LID in Parkinson's disease. Blockade of striatal CaV1.3 calcium channels can prevent spine loss and significantly diminish LID in parkinsonian rats. While pharmacological antagonism with FDA approved CaV1 L-type channel antagonist dihydropyridine (DHP) drugs (e.g, isradipine) are potentially antidyskinetic, pharmacologic limitations of current drugs may result in suboptimal efficacy. To provide optimal CaV1.3 antagonism, we investigated the ability of a dual pharmacological approach to more potently antagonize these channels. Specifically, quinpirole, a D2/D3-type dopamine receptor (D2/3R) agonist, has been demonstrated to significantly reduce calcium current activity at CaV1.3 channels in MSNs of rats by a mechanism distinct from DHPs. We hypothesized that dual inhibition of striatal CaV1.3 channels using the DHP drug isradipine combined with the D2/D3 dopamine receptor agonist quinpirole prior to, and in conjunction with, levodopa would be more effective at preventing structural modifications of dendritic spines and providing more stable LID prevention. For these proof-of-principle studies, rats with unilateral nigrostriatal lesions received daily administration of vehicle, isradipine, quinpirole, or isradipine + quinpirole prior to, and concurrent with, levodopa. Development of LID and morphological analysis of dendritic spines were assessed. Contrary to our hypothesis, quinpirole monotherapy was the most effective at reducing dyskinesia severity and preventing abnormal mushroom spine formation on MSNs, a structural phenomenon previously associated with LID. Notably, the antidyskinetic efficacy of quinpirole monotherapy was lost in the presence of isradipine co-treatment. These findings suggest that D2/D3 dopamine receptor agonists when given in combination with levodopa and initiated in early-stage Parkinson's disease may provide long-term protection against LID. The negative interaction of isradipine with quinpirole suggests a potential cautionary note for co-administration of these drugs in a clinical setting.
Collapse
Affiliation(s)
- Timothy J Collier
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, 220 Cherry St. S.E., Grand Rapids, MI 49503, USA.
| | - Lauren Begg
- Department of Biomedical Sciences, Grand Valley State University, 1 Campus Dr., Allendale, MI 49401, USA
| | - Jennifer A Stancati
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA
| | - Natosha M Mercado
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA
| | - Rhyomi C Sellnow
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA; Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA
| | - Ivette M Sandoval
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, 220 Cherry St. S.E., Grand Rapids, MI 49503, USA.
| | - Caryl E Sortwell
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, 220 Cherry St. S.E., Grand Rapids, MI 49503, USA
| | - Kathy Steece-Collier
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, 220 Cherry St. S.E., Grand Rapids, MI 49503, USA
| |
Collapse
|
|
8
|
Keine C, Radulovic T, Al-Yaari M, Young SM. Confocal Imaging and 3D Reconstruction to Determine How Genetic Perturbations Impact Presynaptic Morphology at the Mouse Calyx of Held. Bio Protoc 2023; 13:e4799. [PMID: 37849785 PMCID: PMC10577601 DOI: 10.21769/bioprotoc.4799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 06/05/2023] [Accepted: 06/08/2023] [Indexed: 10/19/2023] Open
Abstract
Neurons communicate via synapses-specialized structures that consist of a presynaptic terminal of one neuron and a postsynaptic terminal of another. As knowledge is emerging that mutations in molecules that regulate synaptic function underpin many neurological disorders, it is crucial to elucidate the molecular mechanisms regulating synaptic function to understand synaptic strength, plasticity, modulation, and pathology, which ultimately impact neuronal circuit output and behavior. The presynaptic calyx of Held is a large glutamatergic presynaptic terminal in the auditory brainstem, which due to its accessibility and the possibility to selectively perform molecular perturbations on it, is an ideal model to study the role of presynaptic proteins in regulating synaptic function. In this protocol, we describe the use of confocal imaging and three-dimensional reconstruction of the calyx of Held to assess alterations in gross morphology following molecular perturbation. Using viral-vector delivery to perform molecular perturbations at distinct developmental time points, we provide a fast and cost-effective method to investigate how presynaptic proteins regulate gross morphology such as surface area and synapse volume throughout the lifetime of a neuronal circuit. Key features Confocal imaging and 3D reconstruction of presynaptic terminals. Used with a virus-mediated expression of mEGFP to achieve efficient, cell-type specific labeling of the presynaptic compartment. Protocol was developed with the calyx of Held but is suitable for pre- and postsynaptic compartments of various neurons across multiple mammalian and invertebrate species.
Collapse
Affiliation(s)
- Christian Keine
- Department of Anatomy and Cell Biology, University of
Iowa, Iowa City, IA, USA
- Department of Human Medicine, University of
Oldenburg, Oldenburg, Germany
- Research Center Neurosensory Science, Oldenburg,
Germany
| | - Tamara Radulovic
- Department of Anatomy and Cell Biology, University of
Iowa, Iowa City, IA, USA
- Department of Human Medicine, University of
Oldenburg, Oldenburg, Germany
- Research Center Neurosensory Science, Oldenburg,
Germany
| | - Mohammed Al-Yaari
- Department of Anatomy and Cell Biology, University of
Iowa, Iowa City, IA, USA
| | - Samuel M. Young
- Department of Anatomy and Cell Biology, University of
Iowa, Iowa City, IA, USA
- Department of Otolaryngology, Iowa Neuroscience
Institute, University of Iowa, Iowa City, IA, USA
| |
Collapse
|
|
9
|
TREM2 and Microglia Contribute to the Synaptic Plasticity: from Physiology to Pathology. Mol Neurobiol 2023; 60:512-523. [PMID: 36318443 DOI: 10.1007/s12035-022-03100-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 10/20/2022] [Indexed: 11/07/2022]
Abstract
Synapses are bridges for information transmission in the central nervous system (CNS), and synaptic plasticity is fundamental for the normal function of synapses, contributing substantially to learning and memory. Numerous studies have proven that microglia can participate in the occurrence and progression of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), by regulating synaptic plasticity. In this review, we summarize the main characteristics of synapses and synaptic plasticity under physiological and pathological conditions. We elaborate the origin and development of microglia and the two well-known microglial signaling pathways that regulate synaptic plasticity. We also highlight the unique role of triggering receptor expressed on myeloid cells 2 (TREM2) in microglia-mediated regulation of synaptic plasticity and its relationship with AD. Finally, we propose four possible ways in which TREM2 is involved in regulating synaptic plasticity. This review will help researchers understand how NDDs develop from the perspective of synaptic plasticity.
Collapse
|
|
10
|
Zhang X, Zhou J, Xu W, Zhan W, Zou H, Lin J. Transcriptomic and Behavioral Studies of Small Yellow Croaker ( Larimichthyspolyactis) in Response to Noise Exposure. Animals (Basel) 2022; 12:2061. [PMID: 36009652 PMCID: PMC9405241 DOI: 10.3390/ani12162061] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/28/2022] [Accepted: 08/11/2022] [Indexed: 11/21/2022] Open
Abstract
Noise has the potential to induce physiological stress in marine fishes, which may lead to all sorts of ecological consequences. In the current study, we used the RNA-sequencing (RNA-seq) method to sequence the whole transcriptome of the brain in small yellow croaker (Larimichthys polyactis). The animals were exposed to a mix of noises produced by different types of boat played back in a tank, then the brain tissues were collected after the fish had been exposed to a 120 dB noise for 0.5 h. In total, 762 differently expressed genes (DEGs) between the two groups were identified, including 157 up regulated and 605 down regulated genes in the noise exposure group compared with the control group. Gene ontology (GO) enrichment analysis indicated that the most up regulated gene categories included synaptic membranes, receptor-mediated endocytosis and the neurotransmitter secretion process. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways found that endocytosis, cell adhesion molecules and the extracellular matrix (ECM) receptor interaction pathway were over-represented. Specifically, ECM-related genes, including lamin2, lamin3, lamin4, coll1a2, coll5a1 and col4a5 were down regulated in the noise exposure group, implying the impaired composition of the ECM. In addition, the behavioral experiment revealed that L. polyactis exhibited avoidance behaviors to run away from the noise source at the beginning of the noise exposure period. At the end of the noise exposure period, L. polyactis kept motionless on the surface of the water and lost the ability to keep their balance. Taken together, our results indicate that exposure to noise stress contributes to neurological dysfunction in the brain and impaired locomotor ability in L. polyactis.
Collapse
Affiliation(s)
- Xuguang Zhang
- Engineering Technology Research Center of Marine Ranching, College of Marine Ecology and Environment, Shanghai Ocean University, Shanghai 201306, China
| | - Jun Zhou
- Engineering Technology Research Center of Marine Ranching, College of Marine Ecology and Environment, Shanghai Ocean University, Shanghai 201306, China
| | - Wengang Xu
- School of Ocean, Yantai University, Yantai 264005, China
| | - Wei Zhan
- Institute of Hydrobiology, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China
| | - Huafeng Zou
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China
- The Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China
| | - Jun Lin
- Engineering Technology Research Center of Marine Ranching, College of Marine Ecology and Environment, Shanghai Ocean University, Shanghai 201306, China
| |
Collapse
|
|
11
|
Wu XL, Yan QJ, Zhu F. Abnormal synaptic plasticity and impaired cognition in schizophrenia. World J Psychiatry 2022; 12:541-557. [PMID: 35582335 PMCID: PMC9048451 DOI: 10.5498/wjp.v12.i4.541] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/28/2021] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia (SCZ) is a severe mental illness that affects several brain domains with relation to cognition and behaviour. SCZ symptoms are typically classified into three categories, namely, positive, negative, and cognitive. The etiology of SCZ is thought to be multifactorial and poorly understood. Accumulating evidence has indicated abnormal synaptic plasticity and cognitive impairments in SCZ. Synaptic plasticity is thought to be induced at appropriate synapses during memory formation and has a critical role in the cognitive symptoms of SCZ. Many factors, including synaptic structure changes, aberrant expression of plasticity-related genes, and abnormal synaptic transmission, may influence synaptic plasticity and play vital roles in SCZ. In this article, we briefly summarize the morphology of the synapse, the neurobiology of synaptic plasticity, and the role of synaptic plasticity, and review potential mechanisms underlying abnormal synaptic plasticity in SCZ. These abnormalities involve dendritic spines, postsynaptic density, and long-term potentiation-like plasticity. We also focus on cognitive dysfunction, which reflects impaired connectivity in SCZ. Additionally, the potential targets for the treatment of SCZ are discussed in this article. Therefore, understanding abnormal synaptic plasticity and impaired cognition in SCZ has an essential role in drug therapy.
Collapse
Affiliation(s)
- Xiu-Lin Wu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Qiu-Jin Yan
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| |
Collapse
|
|
12
|
Wang W, Zhang L, Deng C, Chen F, Yu Q, Hu Y, Lu Q, Li P, Zhang A. In utero exposure to methylmercury impairs cognitive function in adult offspring: Insights from proteomic modulation. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 231:113191. [PMID: 35051767 DOI: 10.1016/j.ecoenv.2022.113191] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 01/09/2022] [Accepted: 01/10/2022] [Indexed: 06/14/2023]
Abstract
Methylmercury (MeHg) is a hazardous substance that has unique neurodevelopmental toxic effects. However, its molecular alteration profile, sensitive response biomarkers, and mechanism of neuronal injury remain largely unknown. Here, the effects of intrauterine methylmercury chloride (low-, medium- and high-dose groups: 0.6 mg/kg/d, 1.2 mg/kg/d, 2.4 mg/ kg /d, respectively) exposure on learning and memory were assessed in offspring rats by behavioral tests, pathological analysis and hippocampal proteomic analysis. The results suggested that intrauterine MeHg exposure impairs spatial learning and memory and leads a significant reduction in the number and dispersion scattered arrangement in the hippocampus of offspring. Furthermore, in the tandem mass tag-based proteomics analysis, compared with the control group, a total of 74 differentially expressed proteins (DEPs) were found in the MeHg exposure groups; specifically, 32 down-regulated and 42 up-regulated proteins were identified. In addition, the pathways enrichment analysis indicated that these DEPs are implicated in several biological processes, such as synaptic plasticity and energy metabolism, as well as various molecular functional categories. Simultaneously, MeHg reduced the postsynaptic density, diminished the active zone, amplified the synaptic cleft and changed the synaptic interface of pyramidal cells. Western blot analysis further revealed that MeHg significantly reduced the levels of Forkhead box protein (FOXP2), Synaptophysin (SYP) and Postsynaptic density protein 95 (PSD-95), and down-regulated the N-methyl-D-aspartate receptor 1 (NMDAR1), N-methyl-D-aspartate receptor 2 A (NR2A) and N-methyl-D-aspartate receptor 2B (NR2B). In general, from a functional perspective, most overlapping proteins were related to NMDA receptor-mediated glutamatergic signaling, which is an excitotoxicity mechanism known to influence learning and memory. These discoveries contribute to our understanding of the relationship between MeHg and cognitive deficits and provide insight into the protein mediators of this relationship and possible prospective early biomarkers.
Collapse
Affiliation(s)
- Wenjuan Wang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, PR China.
| | - Li Zhang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, PR China
| | - Caiyun Deng
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, PR China
| | - Fang Chen
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, PR China
| | - Qing Yu
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, PR China; State Key Laboratory of Environmental Geochemistry, Institute of Geochemistry, Chinese Academy of Sciences, Guiyang 550081, PR China
| | - Yi Hu
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, PR China
| | - Qin Lu
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, PR China
| | - Ping Li
- State Key Laboratory of Environmental Geochemistry, Institute of Geochemistry, Chinese Academy of Sciences, Guiyang 550081, PR China
| | - Aihua Zhang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, PR China.
| |
Collapse
|
|
13
|
Mu L, Cai J, Gu B, Yu L, Li C, Liu QS, Zhao L. Treadmill Exercise Prevents Decline in Spatial Learning and Memory in 3×Tg-AD Mice through Enhancement of Structural Synaptic Plasticity of the Hippocampus and Prefrontal Cortex. Cells 2022; 11:244. [PMID: 35053360 PMCID: PMC8774241 DOI: 10.3390/cells11020244] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 12/22/2021] [Accepted: 01/08/2022] [Indexed: 01/27/2023] Open
Abstract
Alzheimer's disease (AD) is characterized by deficits in learning and memory. A pathological feature of AD is the alterations in the number and size of synapses, axon length, dendritic complexity, and dendritic spine numbers in the hippocampus and prefrontal cortex. Treadmill exercise can enhance synaptic plasticity in mouse or rat models of stroke, ischemia, and dementia. The aim of this study was to examine the effects of treadmill exercise on learning and memory, and structural synaptic plasticity in 3×Tg-AD mice, a mouse model of AD. Here, we show that 12 weeks treadmill exercise beginning in three-month-old mice improves spatial working memory in six-month-old 3×Tg-AD mice, while non-exercise six-month-old 3×Tg-AD mice exhibited impaired spatial working memory. To investigate potential mechanisms for the treadmill exercise-induced improvement of spatial learning and memory, we examined structural synaptic plasticity in the hippocampus and prefrontal cortex of six-month-old 3×Tg-AD mice that had undergone 12 weeks of treadmill exercise. We found that treadmill exercise led to increases in synapse numbers, synaptic structural parameters, the expression of synaptophysin (Syn, a presynaptic marker), the axon length, dendritic complexity, and the number of dendritic spines in 3×Tg-AD mice and restored these parameters to similar levels of non-Tg control mice without treadmill exercise. In addition, treadmill exercise also improved these parameters in non-Tg control mice. Strengthening structural synaptic plasticity may represent a potential mechanism by which treadmill exercise prevents decline in spatial learning and memory and synapse loss in 3×Tg-AD mice.
Collapse
Affiliation(s)
- Lianwei Mu
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China; (L.M.); (J.C.); (B.G.); (L.Y.); (C.L.)
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA;
| | - Jiajia Cai
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China; (L.M.); (J.C.); (B.G.); (L.Y.); (C.L.)
| | - Boya Gu
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China; (L.M.); (J.C.); (B.G.); (L.Y.); (C.L.)
| | - Laikang Yu
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China; (L.M.); (J.C.); (B.G.); (L.Y.); (C.L.)
| | - Cui Li
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China; (L.M.); (J.C.); (B.G.); (L.Y.); (C.L.)
- School of Physical Education (Main Campus), Zhengzhou University, Zhengzhou 450001, China
| | - Qing-Song Liu
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA;
| | - Li Zhao
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China; (L.M.); (J.C.); (B.G.); (L.Y.); (C.L.)
| |
Collapse
|
|
14
|
Khan H, Beck C, Kunze A. Multi-curvature micropatterns unveil distinct calcium and mitochondrial dynamics in neuronal networks. LAB ON A CHIP 2021; 21:1164-1174. [PMID: 33543185 PMCID: PMC7990709 DOI: 10.1039/d0lc01205j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Tangential curvatures are a key geometric feature of tissue folds in the human cerebral cortex. In the brain, these smoother and firmer bends are called gyri and sulci and form distinctive curved tissue patterns imposing a mechanical stimulus on neuronal networks. This stimulus is hypothesized to be essential for proper brain cell function but lacks in most standard neuronal cell assays. A variety of soft lithographic micropatterning techniques can be used to integrate round geometries in cell assays. Most microfabricated patterns, however, focus only on a small set of defined curvatures. In contrast, curvatures in the brain span a wide physical range, leaving it unknown which precise role distinct curvatures may play on neuronal cell signaling. Here we report a hydrogel-based multi-curvature design consisting of over twenty bands of distinct parallel curvature ranges to precisely engineer neuronal networks' growth and signaling under patterns of arcs. Monitoring calcium and mitochondrial dynamics in primary rodent neurons grown over two weeks in the multi-curvature patterns, we found that static calcium signaling was locally attenuated under higher curvatures (k > 0.01 μm-1). In contrast, to randomize growth, transient calcium signaling showed higher synchronicity when neurons formed networks in confined multi-curvature patterns. Additionally, we found that mitochondria showed lower motility under high curvatures (k > 0.01 μm-1) than under lower curvatures (k < 0.01 μm-1). Our results demonstrate how sensitive neuronal cell function may be linked and controlled through specific curved geometric features. Furthermore, the hydrogel-based multi-curvature design possesses high compatibility with various surfaces, allowing a flexible integration of geometric features into next-generation neuro devices, cell assays, tissue engineering, and implants.
Collapse
Affiliation(s)
- Hammad Khan
- Department of Electrical and Computer Engineering, Montana State University, Bozeman, Montana 59717, USA.
| | | | | |
Collapse
|
|
15
|
Glutamatergic Dysfunction and Synaptic Ultrastructural Alterations in Schizophrenia and Autism Spectrum Disorder: Evidence from Human and Rodent Studies. Int J Mol Sci 2020; 22:ijms22010059. [PMID: 33374598 PMCID: PMC7793137 DOI: 10.3390/ijms22010059] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/15/2020] [Accepted: 12/22/2020] [Indexed: 12/12/2022] Open
Abstract
The correlation between dysfunction in the glutamatergic system and neuropsychiatric disorders, including schizophrenia and autism spectrum disorder, is undisputed. Both disorders are associated with molecular and ultrastructural alterations that affect synaptic plasticity and thus the molecular and physiological basis of learning and memory. Altered synaptic plasticity, accompanied by changes in protein synthesis and trafficking of postsynaptic proteins, as well as structural modifications of excitatory synapses, are critically involved in the postnatal development of the mammalian nervous system. In this review, we summarize glutamatergic alterations and ultrastructural changes in synapses in schizophrenia and autism spectrum disorder of genetic or drug-related origin, and briefly comment on the possible reversibility of these neuropsychiatric disorders in the light of findings in regular synaptic physiology.
Collapse
|
|
16
|
Pérez-Villegas EM, Pérez-Rodríguez M, Negrete-Díaz JV, Ruiz R, Rosa JL, de Toledo GA, Rodríguez-Moreno A, Armengol JA. HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory. Front Neuroanat 2020; 14:592797. [PMID: 33328904 PMCID: PMC7710975 DOI: 10.3389/fnana.2020.592797] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 10/23/2020] [Indexed: 11/23/2022] Open
Abstract
Mutations in the human HERC1 E3 ubiquitin ligase protein develop intellectual disability. The tambaleante (tbl) mouse carries a HERC1 mutation characterized by cerebellar ataxia due of adult cerebellar Purkinje cells death by extensive autophagy. Our previous studies demonstrated that both the neuromuscular junction and the peripheral nerve myelin sheaths are also affected in this mutant. Moreover, there are signs of dysregulated autophagy in the central nervous system in the tbl mouse, affecting spinal cord motor neurons, and pyramidal neurons of the neocortex and the hippocampal CA3 region. The tbl mutation affects associative learning, with absence of short- and long-term potentiation in the lateral amygdala, altered spinogenesis in their neurons, and a dramatic decrease in their glutamatergic input. To assess whether other brain areas engaged in learning processes might be affected by the tbl mutation, we have studied the tbl hippocampus using behavioral tests, ex vivo electrophysiological recordings, immunohistochemistry, the Golgi-Cox method and transmission electron microscopy. The tbl mice performed poorly in the novel-object recognition, T-maze and Morris water maze tests. In addition, there was a decrease in glutamatergic input while the GABAergic one remains unaltered in the hippocampal CA1 region of tbl mice, accompanied by changes in the dendritic spines, and signs of cellular damage. Moreover, the proportions of immature and mature neurons in the dentate gyrus of the tbl hippocampus differ relative to the control mice. Together, these observations demonstrate the important role of HERC1 in regulating synaptic activity during learning.
Collapse
Affiliation(s)
- Eva M. Pérez-Villegas
- Department of Physiology, Anatomy and Cell Biology, Universidad Pablo de Olavide, Seville, Spain
| | - Mikel Pérez-Rodríguez
- Department of Physiology, Anatomy and Cell Biology, Universidad Pablo de Olavide, Seville, Spain
| | - José V. Negrete-Díaz
- Department of Physiology, Anatomy and Cell Biology, Universidad Pablo de Olavide, Seville, Spain
- División de Ciencias de la Salud e Ingenierías, Universidad de Guanajuato, Guanajuato, Mexico
| | - Rocío Ruiz
- Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Seville, Seville, Spain
- Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
| | - Jose Luis Rosa
- Departament de Ciències Fisiològiques, IBIDELL, Universitat de Barcelona, Barcelona, Spain
| | | | - Antonio Rodríguez-Moreno
- Department of Physiology, Anatomy and Cell Biology, Universidad Pablo de Olavide, Seville, Spain
| | - José A. Armengol
- Department of Physiology, Anatomy and Cell Biology, Universidad Pablo de Olavide, Seville, Spain
| |
Collapse
|
|
17
|
Ranneva SV, Maksimov VF, Korostyshevskaja IM, Lipina TV. Lack of synaptic protein, calsyntenin‐2, impairs morphology of synaptic complexes in mice. Synapse 2019; 74:e22132. [DOI: 10.1002/syn.22132] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 09/05/2019] [Accepted: 09/11/2019] [Indexed: 12/31/2022]
Affiliation(s)
- Svetlana V. Ranneva
- Federal State Budgetary Scientific Institution Scientific Research Institute of Physiology and Basic Medicine Novosibirsk Russia
| | - Valeriy F. Maksimov
- Federal State Budgetary Scientific Institution Scientific Research Institute of Physiology and Basic Medicine Novosibirsk Russia
| | - Irina M. Korostyshevskaja
- Federal State Budgetary Scientific Institution Scientific Research Institute of Physiology and Basic Medicine Novosibirsk Russia
| | - Tatiana V. Lipina
- Federal State Budgetary Scientific Institution Scientific Research Institute of Physiology and Basic Medicine Novosibirsk Russia
- Department of Medicine and Psychology Novosibirsk State University Novosibirsk Russia
- Department of Pharmacology and Toxicology University of Toronto Toronto Ontario Canada
| |
Collapse
|
|
18
|
Di G, Liu G, Xu Y, Kim H. Effects of combined traffic noise on the synaptic ultrastructure and expressions of p-CaMKII and NMDAR1 in the hippocampus of young SD rats. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2019; 26:22030-22039. [PMID: 31140091 DOI: 10.1007/s11356-019-05457-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 05/14/2019] [Indexed: 06/09/2023]
Abstract
In order to explore the effects of combined traffic noise (CTN) on learning and memory function, young Sprague-Dawley (SD) rats were exposed to CTN from highway and high-speed railway for 52 days, whose day-night equivalent continuous A-weighted sound pressure level (Ldn) was 70 dB(A) (corresponding sound pressure level was 80 dB). The synaptic ultrastructure and the expressions of phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII) and N-methyl-D-aspartate receptor 1 (NMDAR1 or NR1) in the hippocampus were tested by transmission electron microscopy (TEM) and Western blot, respectively. Results showed that there was no significant difference in the synaptic ultrastructure and the expressions of p-CaMKII and NR1 in the hippocampus of young rats between the experimental group and control group. Compared with single high-speed railway noise (HSRN) with Ldn of 70 dB(A), CTN had less influences on learning and memory function, which was closely related to smaller intermittency of CTN and less anxiety caused by CTN. In comparison with white noise with a sound pressure level of 80 dB, CTN had less impacts on learning and memory function, which was mainly associated with CTN's smaller R-weighted sound pressure level based on rats' auditory sensitivity.
Collapse
Affiliation(s)
- Guoqing Di
- Department of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, 310058, People's Republic of China.
| | - Guangxiang Liu
- Department of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, 310058, People's Republic of China
| | - Yaqian Xu
- Department of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, 310058, People's Republic of China
| | - Hakbong Kim
- Department of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, 310058, People's Republic of China
| |
Collapse
|
|
19
|
Wolf C, Weth A, Walcher S, Lax C, Baumgartner W. Modeling of Zinc Dynamics in the Synaptic Cleft: Implications for Cadherin Mediated Adhesion and Synaptic Plasticity. Front Mol Neurosci 2018; 11:306. [PMID: 30233309 PMCID: PMC6131644 DOI: 10.3389/fnmol.2018.00306] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 08/13/2018] [Indexed: 12/18/2022] Open
Abstract
While the numerous influences of synaptically released zinc on synaptic efficiency during long-term potentiation have been discussed by many authors already, we focused on the possible effect of zinc on cadherins and therefore its contribution to morphological changes in the context of synaptic plasticity. The difficulty with gaining insights into the dynamics of zinc-cadherin interaction is the inability to directly observe it on a suitable timescale. Therefore our approach was to establish an analytical model of the zinc diffusion dynamics in the synaptic cleft and experimentally validate, if the theoretical concentrations at the periphery of the synaptic cleft are sufficient to significantly modulate cadherin-mediated adhesion. Our results emphasize, that synaptically released zinc might have a strong accelerating effect on the morphological changes involved in long-term synaptic plasticity. The approach presented here might also prove useful for investigations on other synaptically released trace metals.
Collapse
Affiliation(s)
- Christoph Wolf
- Institute of Medical Biomechatronics, Johannes Kepler University Linz, Linz, Austria
| | - Agnes Weth
- Institute of Medical Biomechatronics, Johannes Kepler University Linz, Linz, Austria
| | | | - Christian Lax
- Lehrstuhl A für Mathematik, RWTH-Aachen University, Aachen, Germany
| | - Werner Baumgartner
- Institute of Medical Biomechatronics, Johannes Kepler University Linz, Linz, Austria
| |
Collapse
|
|
20
|
Jawaid S, Kidd GJ, Wang J, Swetlik C, Dutta R, Trapp BD. Alterations in CA1 hippocampal synapses in a mouse model of fragile X syndrome. Glia 2018; 66:789-800. [PMID: 29274095 PMCID: PMC5812820 DOI: 10.1002/glia.23284] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 11/29/2017] [Accepted: 12/01/2017] [Indexed: 12/16/2022]
Abstract
Fragile X Syndrome (FXS) is the major cause of inherited mental retardation and the leading genetic cause of Autism spectrum disorders. FXS is caused by mutations in the Fragile X Mental Retardation 1 (Fmr1) gene, which results in transcriptional silencing of Fragile X Mental Retardation Protein (FMRP). To elucidate cellular mechanisms involved in the pathogenesis of FXS, we compared dendritic spines in the hippocampal CA1 region of adult wild-type (WT) and Fmr1 knockout (Fmr1-KO) mice. Using diolistic labeling, confocal microscopy, and three-dimensional electron microscopy, we show a significant increase in the diameter of secondary dendrites, an increase in dendritic spine density, and a decrease in mature dendritic spines in adult Fmr1-KO mice. While WT and Fmr1-KO mice had the same mean density of spines, the variance in spine density was three times greater in Fmr1-KO mice. Reduced astrocyte participation in the tripartite synapse and less mature post-synaptic densities were also found in Fmr1-KO mice. We investigated whether the increase in synaptic spine density was associated with altered synaptic pruning during development. Our data are consistent with reduced microglia-mediated synaptic pruning in the CA1 region of Fmr1-KO hippocampi when compared with WT littermates at postnatal day 21, which is the peak period of synaptic pruning in the mouse hippocampus. Collectively, these results support abnormal synaptogenesis and synaptic remodeling in mice deficient in FMRP. Deficits in the maturation and distribution of synaptic spines on dendrites of CA1 hippocampal neurons may play a role in the intellectual disabilities associated with FXS.
Collapse
Affiliation(s)
- Safdar Jawaid
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Grahame J Kidd
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Jing Wang
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Carrie Swetlik
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Ranjan Dutta
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Bruce D Trapp
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| |
Collapse
|
|
21
|
Zhao F, Liao Y, Tang H, Piao J, Wang G, Jin Y. Effects of developmental arsenite exposure on hippocampal synapses in mouse offspring. Metallomics 2018; 9:1394-1412. [PMID: 28901367 DOI: 10.1039/c7mt00053g] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
arsenite. The thickness of the postsynaptic density (PSD) decreased, whereas the width of the synaptic cleft widened significantly in arsenite exposure groups. Moreover, protein expression of both PSD-95 and SYP decreased significantly in arsenite exposure groups. In conclusion, the results of this study demonstrated that developmental arsenite exposure could depress the expression of synaptic proteins, subsequently cause alteration in synaptic structures, and finally contribute to arsenite-induced deficits in spatial learning and memory ability in mouse offspring.
Collapse
Affiliation(s)
- Fenghong Zhao
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, People's Republic of China.
| | | | | | | | | | | |
Collapse
|
|
22
|
Huang W, Fang YW, Yin Y, Tian B, Zhao W, Hou C, Ma C, Li Q, Tsymbal EY, Duan CG, Li X. Solid-State Synapse Based on Magnetoelectrically Coupled Memristor. ACS APPLIED MATERIALS & INTERFACES 2018; 10:5649-5656. [PMID: 29368507 DOI: 10.1021/acsami.7b18206] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Brain-inspired computing architectures attempt to emulate the computations performed in the neurons and the synapses in the human brain. Memristors with continuously tunable resistances are ideal building blocks for artificial synapses. Through investigating the memristor behaviors in a La0.7Sr0.3MnO3/BaTiO3/La0.7Sr0.3MnO3 multiferroic tunnel junction, it was found that the ferroelectric domain dynamics characteristics are influenced by the relative magnetization alignment of the electrodes, and the interfacial spin polarization is manipulated continuously by ferroelectric domain reversal, enriching our understanding of the magnetoelectric coupling fundamentally. This creates a functionality that not only the resistance of the memristor but also the synaptic plasticity form can be further manipulated, as demonstrated by the spike-timing-dependent plasticity investigations. Density functional theory calculations are carried out to describe the obtained magnetoelectric coupling, which is probably related to the Mn-Ti intermixing at the interfaces. The multiple and controllable plasticity characteristic in a single artificial synapse, to resemble the synaptic morphological alteration property in a biological synapse, will be conducive to the development of artificial intelligence.
Collapse
Affiliation(s)
- Weichuan Huang
- Hefei National Laboratory for Physical Sciences at the Microscale, Department of Physics, University of Science and Technology of China , Hefei 230026, China
| | - Yue-Wen Fang
- Key Laboratory of Polar Materials and Devices, Ministry of Education, Department of Electronic Engineering, East China Normal University , Shanghai 200241, China
| | - Yuewei Yin
- Hefei National Laboratory for Physical Sciences at the Microscale, Department of Physics, University of Science and Technology of China , Hefei 230026, China
- Department of Physics and Astronomy, University of Nebraska , Lincoln, Nebraska 68588, United States
| | - Bobo Tian
- Key Laboratory of Polar Materials and Devices, Ministry of Education, Department of Electronic Engineering, East China Normal University , Shanghai 200241, China
| | - Wenbo Zhao
- Hefei National Laboratory for Physical Sciences at the Microscale, Department of Physics, University of Science and Technology of China , Hefei 230026, China
| | - Chuangming Hou
- Hefei National Laboratory for Physical Sciences at the Microscale, Department of Physics, University of Science and Technology of China , Hefei 230026, China
| | - Chao Ma
- Hefei National Laboratory for Physical Sciences at the Microscale, Department of Physics, University of Science and Technology of China , Hefei 230026, China
| | - Qi Li
- Department of Physics, Pennsylvania State University , University Park 16802, United States
| | - Evgeny Y Tsymbal
- Department of Physics and Astronomy, University of Nebraska , Lincoln, Nebraska 68588, United States
| | - Chun-Gang Duan
- Key Laboratory of Polar Materials and Devices, Ministry of Education, Department of Electronic Engineering, East China Normal University , Shanghai 200241, China
- Collaborative Innovation Center of Extreme Optics, Shanxi University , Shanxi 030006, China
| | - Xiaoguang Li
- Hefei National Laboratory for Physical Sciences at the Microscale, Department of Physics, University of Science and Technology of China , Hefei 230026, China
- Collaborative Innovation Center of Advanced Microstructures , Nanjing 210093, China
| |
Collapse
|
|
23
|
Jarero-Basulto JJ, Gasca-Martínez Y, Rivera-Cervantes MC, Ureña-Guerrero ME, Feria-Velasco AI, Beas-Zarate C. Interactions Between Epilepsy and Plasticity. Pharmaceuticals (Basel) 2018; 11:ph11010017. [PMID: 29414852 PMCID: PMC5874713 DOI: 10.3390/ph11010017] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 02/01/2018] [Accepted: 02/06/2018] [Indexed: 02/06/2023] Open
Abstract
Undoubtedly, one of the most interesting topics in the field of neuroscience is the ability of the central nervous system to respond to different stimuli (normal or pathological) by modifying its structure and function, either transiently or permanently, by generating neural cells and new connections in a process known as neuroplasticity. According to the large amount of evidence reported in the literature, many stimuli, such as environmental pressures, changes in the internal dynamic steady state of the organism and even injuries or illnesses (e.g., epilepsy) may induce neuroplasticity. Epilepsy and neuroplasticity seem to be closely related, as the two processes could positively affect one another. Thus, in this review, we analysed some neuroplastic changes triggered in the hippocampus in response to seizure-induced neuronal damage and how these changes could lead to the establishment of temporal lobe epilepsy, the most common type of focal human epilepsy.
Collapse
Affiliation(s)
- José J Jarero-Basulto
- Cellular Neurobiology Laboratory, Cell and Molecular Biology Department, CUCBA, University of Guadalajara, 45220 Zapopan, Jalisco, Mexico.
| | - Yadira Gasca-Martínez
- Cellular Neurobiology Laboratory, Cell and Molecular Biology Department, CUCBA, University of Guadalajara, 45220 Zapopan, Jalisco, Mexico.
| | - Martha C Rivera-Cervantes
- Cellular Neurobiology Laboratory, Cell and Molecular Biology Department, CUCBA, University of Guadalajara, 45220 Zapopan, Jalisco, Mexico.
| | - Mónica E Ureña-Guerrero
- Neurotransmission Biology Laboratory, Cell and Molecular Biology Department, CUCBA, University of Guadalajara, 45220 Zapopan, Jalisco, Mexico.
| | - Alfredo I Feria-Velasco
- Cellular Neurobiology Laboratory, Cell and Molecular Biology Department, CUCBA, University of Guadalajara, 45220 Zapopan, Jalisco, Mexico.
| | - Carlos Beas-Zarate
- Development and Neural Regeneration Laboratory, Cell and Molecular Biology Department, CUCBA, University of Guadalajara, 45220 Zapopan, Jalisco, Mexico.
| |
Collapse
|
|
24
|
Wang S, Hu T, Wang Z, Li N, Zhou L, Liao L, Wang M, Liao L, Wang H, Zeng L, Fan C, Zhou H, Xiong K, Huang J, Chen D. Macroglia-derived thrombospondin 2 regulates alterations of presynaptic proteins of retinal neurons following elevated hydrostatic pressure. PLoS One 2017; 12:e0185388. [PMID: 28953973 PMCID: PMC5617560 DOI: 10.1371/journal.pone.0185388] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 09/12/2017] [Indexed: 02/03/2023] Open
Abstract
Many studies on retinal injury and repair following elevated intraocular pressure suggest that the survival ratio of retinal neurons has been improved by various measures. However, the visual function recovery is far lower than expected. The homeostasis of retinal synapses in the visual signal pathway is the key structural basis for the delivery of visual signals. Our previous studies found that complicated changes in the synaptic structure between retinal neurons occurred much earlier than obvious degeneration of retinal ganglion cells in rat retinae. The lack of consideration of these earlier retinal synaptic changes in the rescue strategy may be partly responsible for the limited visual function recovery with the types of protective methods for retinal neurons used following elevated intraocular pressure. Thus, research on the modulatory mechanisms of the synaptic changes after elevated intraocular pressure injury may give new light to visual function rescue. In this study, we found that thrombospondin 2, an important regulator of synaptogenesis in central nervous system development, was distributed in retinal macroglia cells, and its receptor α2δ-1 was in retinal neurons. Cell cultures including mixed retinal macroglia cells/neuron cultures and retinal neuron cultures were exposed to elevated hydrostatic pressure for 2 h. The expression levels of glial fibrillary acidic protein (the marker of activated macroglia cells), thrombospondin 2, α2δ-1 and presynaptic proteins were increased following elevated hydrostatic pressure in mixed cultures, but the expression levels of postsynaptic proteins were not changed. SiRNA targeting thrombospondin 2 could decrease the upregulation of presynaptic proteins induced by the elevated hydrostatic pressure. However, in retinal neuron cultures, elevated hydrostatic pressure did not affect the expression of presynaptic or postsynaptic proteins. Rather, the retinal neuron cultures with added recombinant thrombospondin 2 protein upregulated the level of presynaptic proteins. Finally, gabapentin decreased the expression of presynaptic proteins in mixed cultures by blocking the interaction of thrombospondin 2 and α2δ-1. Taken together, these results indicate that activated macroglia cells may participate in alterations of presynaptic proteins of retinal neurons following elevated hydrostatic pressure, and macroglia-derived thrombospondin 2 may modulate these changes via binding to its neuronal receptor α2δ-1.
Collapse
Affiliation(s)
- Shuchao Wang
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| | - Tu Hu
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| | - Zhen Wang
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| | - Na Li
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| | - Lihong Zhou
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| | - Lvshuang Liao
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| | - Mi Wang
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| | - Libin Liao
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| | - Hui Wang
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| | - Leping Zeng
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| | - Chunling Fan
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| | - Hongkang Zhou
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| | - Jufang Huang
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| | - Dan Chen
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, China
| |
Collapse
|
|
25
|
Han YY, Wang XD, Liu L, Guo HM, Cong W, Yan WW, Huang JN, Xiao P, Li CH. L-type VDCCs participate in behavioral-LTP and memory retention. Neurobiol Learn Mem 2017; 145:75-83. [PMID: 28866469 DOI: 10.1016/j.nlm.2017.08.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 08/09/2017] [Accepted: 08/29/2017] [Indexed: 11/25/2022]
Abstract
Although L-type voltage-dependent calcium channels (VDCCs) have been reported to display different even contrary actions on cognitive functions and long-term potentiation (LTP) formation, there is little information regarding the role of L-type VDCCs in behavioral LTP, a learning-induced LTP model, in the intact brain of freely behaving animals. Here we investigated the effects of verapamil, a non-selective blocker of L-type VDCCs, on behavioral LTP and cognitive functions. Population spikes (PS) were recorded by using electrophysiological methods to examine the role of verapamil in behavioral LTP in the hippocampal dentate gyrus (DG) region. Y-maze assay was used to evaluate the effects of verapamil on learning and memory. Electron microscope was used to observe the changes on synaptic ultrastructural morphology in hippocampal DG area. We found that intrahippocampal verapamil treatments had no significant changes on the PS amplitude during a 90min recordings period. However, intrahippocampal applications of verapamil, including pre- or post-training, reduced behavioral LTP magnitude and memory retention but did not prevent the induction of behavioral LTP and the acquisition of learning. The saline group with behaving trainings showed obvious increases in the number of smile synapses, the length of active zones and the thickness of postsynaptic density as compared to the baseline group, but verapamil with pre-training treatment almost returned these changes to the baseline levels except for the synaptic interface curvature. In conclusion, our results suggest that L-type VDCCs may only contribute to the magnitude of behavioral LTP and the memory maintenance with an activity-independent relationship. L-type VDCCs may be critical to new information long-term storage rather than acquisition in hippocampus.
Collapse
Affiliation(s)
- Yuan-Yuan Han
- School of Life Science, South China Normal University, Guangzhou 510631, China
| | - Xiao-Dong Wang
- School of Life Science, South China Normal University, Guangzhou 510631, China
| | - Li Liu
- School of Life Science, South China Normal University, Guangzhou 510631, China
| | - Hong-Mei Guo
- School of Life Science, South China Normal University, Guangzhou 510631, China
| | - Wei Cong
- Henan Medical Equipment Inspection Institute, Zhengzhou 450003, China
| | - Wen-Wen Yan
- School of Life Science, South China Normal University, Guangzhou 510631, China
| | - Jun-Ni Huang
- School of Life Science, South China Normal University, Guangzhou 510631, China
| | - Peng Xiao
- School of Life Science, South China Normal University, Guangzhou 510631, China.
| | - Chu-Hua Li
- School of Life Science, South China Normal University, Guangzhou 510631, China; Brain Science Institute, South China Normal University, Guangzhou 510631, China.
| |
Collapse
|
|
26
|
Fang Z, Zhu Q, Gu T, Shen X, Yang Y, Liang Y, Zhang Z, Xu X. Anti-androgenic effects of bisphenol-A on spatial memory and synaptic plasticity of the hippocampus in mice. Horm Behav 2017; 93:151-158. [PMID: 28576649 DOI: 10.1016/j.yhbeh.2017.05.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Revised: 05/19/2017] [Accepted: 05/28/2017] [Indexed: 12/31/2022]
Abstract
Bisphenol-A (BPA) is a common environmental endocrine disruptor. Our recent studies found that exposure to BPA in both adolescent and adulthood sex-specifically impaired spatial memory in male mice. In this study, 11-week-old gonadectomied (GDX) male mice daily received subcutaneous injections of testosterone propionate (TP, 0.5mg/kg), TP and BPA (0.4 and 4mg/kg), or vehicle for 45days. The results of Morris water maze task showed that exposure to BPA did not affect the spatial memory of GDX mice but impaired that of sham (4mg/kg/day) and TP-treated GDX mice (0.4mg/kg/day). In addition, BPA reduced the level of testosterone (T) in the serum and brain of sham and TP-treated GDX mice. Exposure to BPA decreased the synaptic density and had an adverse effect on the synaptic interface of the hippocampus in sham and TP-treated GDX mice. The results of western blot analysis further showed that BPA (4mg/kg) reduced the levels of synaptic proteins (synapsin I and PSD-95) and NMDA receptor subunit NR2B in sham and TP-treated GDX mice. BPA decreased the phosphorylation of ERK1/2 but increased the phosphorylation of p38 in sham and TP-treated GDX mice. These results suggest that impairment of spatial memory and adverse effects on synaptic remodeling of hippocampal neurons in males after long-term BPA exposure is related to the anti-androgen effect of BPA. These effects of BPA may be associated with downregulated synaptic proteins and NMDA receptor through inhibiting ERKs and promoting the p38 pathways.
Collapse
Affiliation(s)
- Zhaoqing Fang
- Chemistry and Life Sciences College, Xingzhi College, Zhejiang Provincial Key Laboratory of Ecology, Key laboratory of wildlife biotechnology and conservation and utilization of Zhejiang Province, Zhejiang Normal University, China
| | - Qingjie Zhu
- Chemistry and Life Sciences College, Xingzhi College, Zhejiang Provincial Key Laboratory of Ecology, Key laboratory of wildlife biotechnology and conservation and utilization of Zhejiang Province, Zhejiang Normal University, China
| | - Ting Gu
- Chemistry and Life Sciences College, Xingzhi College, Zhejiang Provincial Key Laboratory of Ecology, Key laboratory of wildlife biotechnology and conservation and utilization of Zhejiang Province, Zhejiang Normal University, China
| | - Xiuying Shen
- School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, China
| | - Yang Yang
- Chemistry and Life Sciences College, Xingzhi College, Zhejiang Provincial Key Laboratory of Ecology, Key laboratory of wildlife biotechnology and conservation and utilization of Zhejiang Province, Zhejiang Normal University, China
| | - Yufeng Liang
- Chemistry and Life Sciences College, Xingzhi College, Zhejiang Provincial Key Laboratory of Ecology, Key laboratory of wildlife biotechnology and conservation and utilization of Zhejiang Province, Zhejiang Normal University, China
| | - Zigui Zhang
- Chemistry and Life Sciences College, Xingzhi College, Zhejiang Provincial Key Laboratory of Ecology, Key laboratory of wildlife biotechnology and conservation and utilization of Zhejiang Province, Zhejiang Normal University, China
| | - Xiaohong Xu
- Chemistry and Life Sciences College, Xingzhi College, Zhejiang Provincial Key Laboratory of Ecology, Key laboratory of wildlife biotechnology and conservation and utilization of Zhejiang Province, Zhejiang Normal University, China.
| |
Collapse
|
|
27
|
Lo FS, Erzurumlu RS. Sensory Activity-Dependent and Sensory Activity-Independent Properties of the Developing Rodent Trigeminal Principal Nucleus. Dev Neurosci 2016; 38:163-170. [PMID: 27287019 DOI: 10.1159/000446395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 04/24/2016] [Indexed: 11/19/2022] Open
Abstract
The whisker-sensory trigeminal central pathway of rodents is an established model for studies of activity-dependent neural plasticity. The first relay station of the pathway is the trigeminal principal nucleus (PrV), the ventral part of which receives sensory inputs mainly from the infraorbital branch of the maxillary trigeminal nerve (ION). Whisker-sensory afferents play an important role in the development of the morphological and physiological properties of PrV neurons. In neonates, deafferentation by ION transection leads to the disruption of whisker-related neural patterns (barrelettes) and cell death within a specific time window (critical period), as revealed by morphological studies. Whisker-sensory inputs control synaptic elimination, postsynaptic AMPA receptor trafficking, astrocyte-mediated synaptogenesis, and receptive-field characteristics of PrV cells, without a postnatal critical period. Sensory activity-dependent synaptic plasticity requires the activation of NMDA receptors and involves the participation of glia. However, the basic physiological properties of PrV neurons, such as cell type-specific ion channels, presynaptic terminal function, postsynaptic NMDA receptor subunit composition, and formation of the inhibitory circuitry, are independent of sensory inputs. Therefore, the first relay station of the whisker sensation is largely mature-like and functional at birth. Delineation of activity-dependent and activity-independent features of the postnatal PrV is important for understanding the development and functional characteristics of downstream trigeminal stations in the thalamus and neocortex. This mini review focuses on such features of the developing rodent PrV.
Collapse
Affiliation(s)
- Fu-Sun Lo
- Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Md., USA
| | | |
Collapse
|
|
28
|
Bosch C, Muhaisen A, Pujadas L, Soriano E, Martínez A. Reelin Exerts Structural, Biochemical and Transcriptional Regulation Over Presynaptic and Postsynaptic Elements in the Adult Hippocampus. Front Cell Neurosci 2016; 10:138. [PMID: 27303269 PMCID: PMC4884741 DOI: 10.3389/fncel.2016.00138] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 05/10/2016] [Indexed: 11/13/2022] Open
Abstract
Reelin regulates neuronal positioning and synaptogenesis in the developing brain, and adult brain plasticity. Here we used transgenic mice overexpressing Reelin (Reelin-OE mice) to perform a comprehensive dissection of the effects of this protein on the structural and biochemical features of dendritic spines and axon terminals in the adult hippocampus. Electron microscopy (EM) revealed both higher density of synapses and structural complexity of both pre- and postsynaptic elements in transgenic mice than in WT mice. Dendritic spines had larger spine apparatuses, which correlated with a redistribution of Synaptopodin. Most of the changes observed in Reelin-OE mice were reversible after blockade of transgene expression, thus supporting the specificity of the observed phenotypes. Western blot and transcriptional analyses did not show major changes in the expression of pre- or postsynaptic proteins, including SNARE proteins, glutamate receptors, and scaffolding and signaling proteins. However, EM immunogold assays revealed that the NMDA receptor subunits NR2a and NR2b, and p-Cofilin showed a redistribution from synaptic to extrasynaptic pools. Taken together with previous studies, the present results suggest that Reelin regulates the structural and biochemical properties of adult hippocampal synapses by increasing their density and morphological complexity and by modifying the distribution and trafficking of major glutamatergic components.
Collapse
Affiliation(s)
- Carles Bosch
- Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of BarcelonaBarcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), MadridSpain; Vall d'Hebron Institut de RecercaBarcelona, Spain
| | - Ashraf Muhaisen
- Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of BarcelonaBarcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), MadridSpain; Vall d'Hebron Institut de RecercaBarcelona, Spain; Institute of Neurosciences, University of BarcelonaBarcelona, Spain
| | - Lluís Pujadas
- Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of BarcelonaBarcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), MadridSpain; Vall d'Hebron Institut de RecercaBarcelona, Spain
| | - Eduardo Soriano
- Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of BarcelonaBarcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), MadridSpain; Vall d'Hebron Institut de RecercaBarcelona, Spain; Institute of Neurosciences, University of BarcelonaBarcelona, Spain; Institució Catalana de Recerca i Estudis Avançats AcademiaBarcelona, Spain
| | - Albert Martínez
- Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona Barcelona, Spain
| |
Collapse
|
|
29
|
Rylander Ottosson D, Lane E. Striatal Plasticity in L-DOPA- and Graft-Induced Dyskinesia; The Common Link? Front Cell Neurosci 2016; 10:16. [PMID: 26903804 PMCID: PMC4744851 DOI: 10.3389/fncel.2016.00016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 01/15/2016] [Indexed: 12/31/2022] Open
Abstract
One of the major symptoms of the neurodegenerative condition Parkinson's disease (PD) is a slowness or loss of voluntary movement, yet frustratingly therapeutic strategies designed to restore movement can result in the development of excessive abnormal movements known as dyskinesia. These dyskinesias commonly develop as a result of pharmacotherapy in the form of L-DOPA administration, but have also been identified following deep brain stimulation (DBS) and intrastriatal cell transplantation. In the case of L-DOPA these movements can be treatment limiting, and whilst they are not long lasting or troubling following DBS, recognition of their development had a near devastating effect on the field of cell transplantation for PD.Understanding the relationship between these therapeutic approaches and the development of dyskinesia may improve our ability to restore function without disabling side effects. Interestingly, despite the fact that dopaminergic cell transplantation repairs many of the changes induced by the disease process and through L-DOPA treatment, there appears to be a relationship between the two. In rodent models of the disease, the severity of dyskinesia induced by L-DOPA prior to the transplantation procedure correlated with post-transplantation, graft-induced dyskinesia. A review of clinical data also suggested that the worse preoperational dyskinesia causes worsened graft-induced dyskinesia (GID). Understanding how these aberrant behaviors come about has been of keen interest to open up these therapeutic options more widely and one major underlying theory is the effects of these approaches on the plasticity of synapses within the basal ganglia. This review uniquely brings together developments in understanding the role of striatal synaptic plasticity in both L-DOPA and GID to guide and stimulate further investigations on the important striatal plasticity.
Collapse
Affiliation(s)
- Daniella Rylander Ottosson
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund UniversityLund, Sweden
| | - Emma Lane
- School of Pharmacy and Pharmaceutical Sciences, Cardiff UniversityCardiff, UK
| |
Collapse
|
|
30
|
Lo FS, Erzurumlu RS. Neonatal sensory nerve injury-induced synaptic plasticity in the trigeminal principal sensory nucleus. Exp Neurol 2016; 275 Pt 2:245-52. [PMID: 25956829 PMCID: PMC4636484 DOI: 10.1016/j.expneurol.2015.04.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 04/29/2015] [Indexed: 11/26/2022]
Abstract
Sensory deprivation studies in neonatal mammals, such as monocular eye closure, whisker trimming, and chemical blockade of the olfactory epithelium have revealed the importance of sensory inputs in brain wiring during distinct critical periods. But very few studies have paid attention to the effects of neonatal peripheral sensory nerve damage on synaptic wiring of the central nervous system (CNS) circuits. Peripheral somatosensory nerves differ from other special sensory afferents in that they are more prone to crush or severance because of their locations in the body. Unlike the visual and auditory afferents, these nerves show regenerative capabilities after damage. Uniquely, damage to a somatosensory peripheral nerve does not only block activity incoming from the sensory receptors but also mediates injury-induced neuro- and glial chemical signals to the brain through the uninjured central axons of the primary sensory neurons. These chemical signals can have both far more and longer lasting effects than sensory blockade alone. Here we review studies which focus on the consequences of neonatal peripheral sensory nerve damage in the principal sensory nucleus of the brainstem trigeminal complex.
Collapse
Affiliation(s)
- Fu-Sun Lo
- Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - Reha S Erzurumlu
- Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| |
Collapse
|
|
31
|
Yu H, Liao Y, Li T, Cui Y, Wang G, Zhao F, Jin Y. Alterations of Synaptic Proteins in the Hippocampus of Mouse Offspring Induced by Developmental Lead Exposure. Mol Neurobiol 2015; 53:6786-6798. [DOI: 10.1007/s12035-015-9597-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2015] [Accepted: 12/01/2015] [Indexed: 12/22/2022]
|
|
32
|
Li XL, Yuan YG, Xu H, Wu D, Gong WG, Geng LY, Wu FF, Tang H, Xu L, Zhang ZJ. Changed Synaptic Plasticity in Neural Circuits of Depressive-Like and Escitalopram-Treated Rats. Int J Neuropsychopharmacol 2015; 18:pyv046. [PMID: 25899067 PMCID: PMC4648155 DOI: 10.1093/ijnp/pyv046] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Although progress has been made in the detection and characterization of neural plasticity in depression, it has not been fully understood in individual synaptic changes in the neural circuits under chronic stress and antidepressant treatment. METHODS Using electron microscopy and Western-blot analyses, the present study quantitatively examined the changes in the Gray's Type I synaptic ultrastructures and the expression of synapse-associated proteins in the key brain regions of rats' depressive-related neural circuit after chronic unpredicted mild stress and/or escitalopram administration. Meanwhile, their depressive behaviors were also determined by several tests. RESULTS The Type I synapses underwent considerable remodeling after chronic unpredicted mild stress, which resulted in the changed width of the synaptic cleft, length of the active zone, postsynaptic density thickness, and/or synaptic curvature in the subregions of medial prefrontal cortex and hippocampus, as well as the basolateral amygdaloid nucleus of the amygdala, accompanied by changed expression of several synapse-associated proteins. Chronic escitalopram administration significantly changed the above alternations in the chronic unpredicted mild stress rats but had little effect on normal controls. Also, there was a positive correlation between the locomotor activity and the maximal synaptic postsynaptic density thickness in the stratum radiatum of the Cornu Ammonis 1 region and a negative correlation between the sucrose preference and the length of the active zone in the basolateral amygdaloid nucleus region in chronic unpredicted mild stress rats. CONCLUSION These findings strongly indicate that chronic stress and escitalopram can alter synaptic plasticity in the neural circuits, and the remodeled synaptic ultrastructure was correlated with the rats' depressive behaviors, suggesting a therapeutic target for further exploration.
Collapse
Affiliation(s)
- Xiao-Li Li
- Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China (Drs Li, Yuan, H. Xu, D. Wu, Gong, Geng, F-F. Wu, Tang, and Zhang); Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China (Dr L. Xu); Graduate School of Chinese Academy of Sciences, Beijing, China (Dr L. Xu)X-L.L. and Y-G.Y. contributed equally to this work
| | - Yong-Gui Yuan
- Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China (Drs Li, Yuan, H. Xu, D. Wu, Gong, Geng, F-F. Wu, Tang, and Zhang); Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China (Dr L. Xu); Graduate School of Chinese Academy of Sciences, Beijing, China (Dr L. Xu)X-L.L. and Y-G.Y. contributed equally to this work
| | - Hua Xu
- Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China (Drs Li, Yuan, H. Xu, D. Wu, Gong, Geng, F-F. Wu, Tang, and Zhang); Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China (Dr L. Xu); Graduate School of Chinese Academy of Sciences, Beijing, China (Dr L. Xu)X-L.L. and Y-G.Y. contributed equally to this work
| | - Di Wu
- Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China (Drs Li, Yuan, H. Xu, D. Wu, Gong, Geng, F-F. Wu, Tang, and Zhang); Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China (Dr L. Xu); Graduate School of Chinese Academy of Sciences, Beijing, China (Dr L. Xu)X-L.L. and Y-G.Y. contributed equally to this work
| | - Wei-Gang Gong
- Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China (Drs Li, Yuan, H. Xu, D. Wu, Gong, Geng, F-F. Wu, Tang, and Zhang); Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China (Dr L. Xu); Graduate School of Chinese Academy of Sciences, Beijing, China (Dr L. Xu)X-L.L. and Y-G.Y. contributed equally to this work
| | - Lei-Yu Geng
- Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China (Drs Li, Yuan, H. Xu, D. Wu, Gong, Geng, F-F. Wu, Tang, and Zhang); Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China (Dr L. Xu); Graduate School of Chinese Academy of Sciences, Beijing, China (Dr L. Xu)X-L.L. and Y-G.Y. contributed equally to this work
| | - Fang-Fang Wu
- Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China (Drs Li, Yuan, H. Xu, D. Wu, Gong, Geng, F-F. Wu, Tang, and Zhang); Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China (Dr L. Xu); Graduate School of Chinese Academy of Sciences, Beijing, China (Dr L. Xu)X-L.L. and Y-G.Y. contributed equally to this work
| | - Hao Tang
- Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China (Drs Li, Yuan, H. Xu, D. Wu, Gong, Geng, F-F. Wu, Tang, and Zhang); Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China (Dr L. Xu); Graduate School of Chinese Academy of Sciences, Beijing, China (Dr L. Xu)X-L.L. and Y-G.Y. contributed equally to this work
| | - Lin Xu
- Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China (Drs Li, Yuan, H. Xu, D. Wu, Gong, Geng, F-F. Wu, Tang, and Zhang); Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China (Dr L. Xu); Graduate School of Chinese Academy of Sciences, Beijing, China (Dr L. Xu)X-L.L. and Y-G.Y. contributed equally to this work
| | - Zhi-Jun Zhang
- Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China (Drs Li, Yuan, H. Xu, D. Wu, Gong, Geng, F-F. Wu, Tang, and Zhang); Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China (Dr L. Xu); Graduate School of Chinese Academy of Sciences, Beijing, China (Dr L. Xu)X-L.L. and Y-G.Y. contributed equally to this work.
| |
Collapse
|
|
33
|
Spejo AB, Oliveira ALR. Synaptic rearrangement following axonal injury: Old and new players. Neuropharmacology 2014; 96:113-23. [PMID: 25445484 DOI: 10.1016/j.neuropharm.2014.11.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 11/03/2014] [Accepted: 11/04/2014] [Indexed: 10/24/2022]
Abstract
Following axotomy, the contact between motoneurons and muscle fibers is disrupted, triggering a retrograde reaction at the neuron cell body within the spinal cord. Together with chromatolysis, a hallmark of such response to injury is the elimination of presynaptic terminals apposing to the soma and proximal dendrites of the injured neuron. Excitatory inputs are preferentially eliminated, leaving the cells under an inhibitory influence during the repair process. This is particularly important to avoid glutamate excitotoxicity. Such shift from transmission to a regeneration state is also reflected by deep metabolic changes, seen by the regulation of several genes related to cell survival and axonal growth. It is unclear, however, how exactly synaptic stripping occurs, but there is substantial evidence that glial cells play an active role in this process. In one hand, immune molecules, such as the major histocompatibility complex (MHC) class I, members of the complement family and Toll-like receptors are actively involved in the elimination/reapposition of presynaptic boutons. On the other hand, plastic changes that involve sprouting might be negatively regulated by extracellular matrix proteins such as Nogo-A, MAG and scar-related chondroitin sulfate proteoglycans. Also, neurotrophins, stem cells, physical exercise and several drugs seem to improve synaptic stability, leading to functional recovery after lesion. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'.
Collapse
Affiliation(s)
- Aline Barroso Spejo
- Laboratory of Nerve Regeneration, Department of Structural and Functional Biology, University of Campinas - UNICAMP, Campinas, SP, Brazil
| | - Alexandre L R Oliveira
- Laboratory of Nerve Regeneration, Department of Structural and Functional Biology, University of Campinas - UNICAMP, Campinas, SP, Brazil.
| |
Collapse
|
|
34
|
Liu Y, Sun Z, Sun S, Duan Y, Shi J, Qi Z, Meng R, Sun Y, Zeng X, Chui D, Ji X. Effects of hypoxic preconditioning on synaptic ultrastructure in mice. Synapse 2014; 69:7-14. [PMID: 25155519 DOI: 10.1002/syn.21777] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 07/21/2014] [Accepted: 08/08/2014] [Indexed: 11/06/2022]
Abstract
Hypoxic preconditioning (HPC) elicits resistance to more drastic subsequent insults, which potentially provide neuroprotective therapeutic strategy, but the underlying mechanisms remain to be fully elucidated. Here, we examined the effects of HPC on synaptic ultrastructure in olfactory bulb of mice. Mice underwent up to five cycles of repeated HPC treatments, and hypoxic tolerance was assessed with a standard gasp reflex assay. As expected, HPC induced an increase in tolerance time. To assess synaptic responses, Western blots were used to quantify protein levels of representative markers for glia, neuron, and synapse, and transmission electron microscopy was used to examine synaptic ultrastructure and mitochondrial density. HPC did not significantly alter the protein levels of astroglial marker (GFAP), neuron-specific markers (GAP43, Tuj-1, and OMP), synaptic number markers (synaptophysin and SNAP25) or the percentage of excitatory synapses versus inhibitory synapses. However, HPC significantly affected synaptic curvature and the percentage of synapses with presynaptic mitochondria, which showed concomitant change pattern. These findings demonstrate that HPC is associated with changes in synaptic ultrastructure.
Collapse
Affiliation(s)
- Yi Liu
- China-America Joint Institute of Neuroscience, CAJIN, Xuanwu Hospital, Capital Medical University, Beijing, China; Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Neuroprotection Research Laboratory, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Liu Y, Liang Z, Liu J, Zou W, Li X, Wang Y, An L. Downregulation of caveolin-1 contributes to the synaptic plasticity deficit in the hippocampus of aged rats. Neural Regen Res 2014; 8:2725-33. [PMID: 25206583 PMCID: PMC4145999 DOI: 10.3969/j.issn.1673-5374.2013.29.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2013] [Accepted: 08/26/2013] [Indexed: 12/11/2022] Open
Abstract
Caveolin-1 is involved in the regulation of synaptic plasticity, but the relationship between its pression and cognitive function during aging remains controversial. To explore the relationship be-tween synaptic plasticity in the aging process and changes in learning and memory, we examined caveolin-1 expression in the hippocampus, cortex and cerebellum of rats at different ages. We also examined the relationship between the expression of caveolin-1 and synaptophysin, a marker of synaptic plasticity. Hippocampal caveolin-1 and synaptophysin expression in aged (22–24 month old) rats was significantly lower than that in young (1 month old) and adult (4 months old) rats. pression levels of both proteins were significantly greater in the cortex of aged rats than in that of young or adult rats, and levels were similar between the three age groups in the cerebellum. Linear regression analysis revealed that hippocampal expression of synaptophysin was associated with memory and learning abilities. Moreover, synaptophysin expression correlated positively with caveolin-1 expression in the hippocampus, cortex and cerebellum. These results confirm that caveolin-1 has a regulatory effect on synaptic plasticity, and suggest that the downregulation of hippocampal caveolin-1 expression causes a decrease in synaptic plasticity during physiological aging.
Collapse
Affiliation(s)
- Yang Liu
- Regenerative Medicine Center, the First Affiliated Hospital, Dalian Medical University, Dalian 116021, Liaoning Province, China
| | - Zhanhua Liang
- Department of Neurology, the First Affiliated Hospital, Dalian Medical University, Dalian 116021, Liaoning Province, China
| | - Jing Liu
- Regenerative Medicine Center, the First Affiliated Hospital, Dalian Medical University, Dalian 116021, Liaoning Province, China
| | - Wei Zou
- Department of Biology, Liaoning Normal University, Dalian 116023, Liaoning Province, China
| | - Xiaoyan Li
- Regenerative Medicine Center, the First Affiliated Hospital, Dalian Medical University, Dalian 116021, Liaoning Province, China
| | - Yachen Wang
- Department of Neurology, the First Affiliated Hospital, Dalian Medical University, Dalian 116021, Liaoning Province, China
| | - Lijia An
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning Province, China
| |
Collapse
|
|
36
|
Barton B, Treister A, Humphrey M, Abedi G, Cramer SC, Brewer AA. Paradoxical visuomotor adaptation to reversed visual input is predicted by BDNF Val66Met polymorphism. J Vis 2014; 14:14.9.4. [PMID: 25104829 DOI: 10.1167/14.9.4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain, influencing neural development, plasticity, and repair (Chen et al., 2004; Thoenen, 1995). The BDNF gene contains a single-nucleotide polymorphism (SNP) called Val(66)Met. The Met allele interferes with intracellular BDNF-trafficking, decreases activity-dependent BDNF secretion, and consequently is often associated with a shift from plasticity to stability in neural circuits (Egan et al., 2003). We investigated the behavioral consequences of the presence of the Met allele by comparing how 40 heterozygous subjects with the Val/Met genotype and 35 homozygous subjects with the Val/Val genotype performed on visuomotor tasks (reaching and navigation) under two conditions: normal vision and completely left-right reversed vision. As expected, subjects did not differ in their short-term ability to learn the tasks with normal vision (p = 0.58). Intuitively, it would be expected that homozygous Val/Val subjects with a propensity for greater BDNF-induced activity-dependent plasticity would learn new tasks more quickly than heterozygous Val/Met subjects with decreased BDNF secretion (Gilbert, Li, & Piech, 2009). However, we found the opposite here. When short-term mechanisms of visuomotor adaptation were engaged to compensate for the misalignment of visual and somatomotor information created by the left-right reversal of vision, heterozygous Val/Met subjects learned significantly more quickly than their homozygous Val/Val counterparts (p = 0.027). Our results demonstrate the paradoxical finding that the presence of the Met allele, which is thought to promote cortical stability, here improves immediate visuomotor adaptation to left-right-reversed visual input.
Collapse
Affiliation(s)
- Brian Barton
- Department of Cognitive Sciences, University of California, Irvine, CA, USA
| | - Andrew Treister
- Department of Neurology, University of California, Irvine, CA, USA
| | - Melanie Humphrey
- Department of Cognitive Sciences, University of California, Irvine, CA, USA
| | - Garen Abedi
- Department of Neurology, University of California, Irvine, CA, USA
| | - Steven C Cramer
- Departments of Anatomy and Neurobiology and Neurology, University of California, Irvine, CA, USA
| | - Alyssa A Brewer
- Department of Cognitive Sciences, University of California, Irvine, CA, USA
| |
Collapse
|
|
37
|
Meyer D, Bonhoeffer T, Scheuss V. Balance and Stability of Synaptic Structures during Synaptic Plasticity. Neuron 2014; 82:430-43. [DOI: 10.1016/j.neuron.2014.02.031] [Citation(s) in RCA: 278] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2014] [Indexed: 12/27/2022]
|
|
38
|
Morice E, Farley S, Poirier R, Dallerac G, Chagneau C, Pannetier S, Hanauer A, Davis S, Vaillend C, Laroche S. Defective synaptic transmission and structure in the dentate gyrus and selective fear memory impairment in the Rsk2 mutant mouse model of Coffin-Lowry syndrome. Neurobiol Dis 2013; 58:156-68. [PMID: 23742761 DOI: 10.1016/j.nbd.2013.05.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Revised: 04/18/2013] [Accepted: 05/27/2013] [Indexed: 12/20/2022] Open
Abstract
The Coffin-Lowry syndrome (CLS) is a syndromic form of intellectual disability caused by loss-of-function of the RSK2 serine/threonine kinase encoded by the rsk2 gene. Rsk2 knockout mice, a murine model of CLS, exhibit spatial learning and memory impairments, yet the underlying neural mechanisms are unknown. In the current study, we examined the performance of Rsk2 knockout mice in cued, trace and contextual fear memory paradigms and identified selective deficits in the consolidation and reconsolidation of hippocampal-dependent fear memories as task difficulty and hippocampal demand increase. Electrophysiological, biochemical and electron microscopy analyses were carried out in the dentate gyrus of the hippocampus to explore potential alterations in neuronal functions and structure. In vivo and in vitro electrophysiology revealed impaired synaptic transmission, decreased network excitability and reduced AMPA and NMDA conductance in Rsk2 knockout mice. In the absence of RSK2, standard measures of short-term and long-term potentiation (LTP) were normal, however LTP-induced CREB phosphorylation and expression of the transcription factors EGR1/ZIF268 were reduced and that of the scaffolding protein SHANK3 was blocked, indicating impaired activity-dependent gene regulation. At the structural level, the density of perforated and non-perforated synapses and of multiple spine boutons was not altered, however, a clear enlargement of spine neck width and post-synaptic densities indicates altered synapse ultrastructure. These findings show that RSK2 loss-of-function is associated in the dentate gyrus with multi-level alterations that encompass modifications of glutamate receptor channel properties, synaptic transmission, plasticity-associated gene expression and spine morphology, providing novel insights into the mechanisms contributing to cognitive impairments in CLS.
Collapse
Affiliation(s)
- Elise Morice
- Centre de Neurosciences Paris-Sud, CNRS, Orsay, France
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Baumgartner W, Osmanagic A, Gebhard M, Kraemer S, Golenhofen N. Different pH-dependencies of the two synaptic adhesion moleculesN-cadherin and cadherin-11 and the possible functional implication for long-term potentiation. Synapse 2013; 67:705-15. [DOI: 10.1002/syn.21679] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 04/17/2013] [Indexed: 11/10/2022]
Affiliation(s)
- Werner Baumgartner
- Department of Cellular Neurobionic; Institute for Biology II; RWTH Aachen, Lukasstrasse 1; 52070; Aachen; Germany
| | - Armin Osmanagic
- Department of Cellular Neurobionic; Institute for Biology II; RWTH Aachen, Lukasstrasse 1; 52070; Aachen; Germany
| | - Marita Gebhard
- Institute of Anatomy and Cell Biology; University of Ulm; Albert-Einstein-Allee 11; 89081; Ulm; Germany
| | - Sandra Kraemer
- Institute of Biochemistry and Molecular Cell Biology; RWTH Aachen; Pauwelsstrasse 30; 52074; Aachen; Germany
| | - Nikola Golenhofen
- Institute of Anatomy and Cell Biology; University of Ulm; Albert-Einstein-Allee 11; 89081; Ulm; Germany
| |
Collapse
|
|
40
|
Xu X, Liu X, Zhang Q, Zhang G, Lu Y, Ruan Q, Dong F, Yang Y. Sex-specific effects of bisphenol-A on memory and synaptic structural modification in hippocampus of adult mice. Horm Behav 2013; 63:766-75. [PMID: 23523742 DOI: 10.1016/j.yhbeh.2013.03.004] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Revised: 03/05/2013] [Accepted: 03/07/2013] [Indexed: 12/16/2022]
Abstract
Humans are routinely exposed to low levels of bisphenol A (BPA), a synthetic xenoestrogen widely used in the production of polycarbonate plastics. The effects of long-term exposure to BPA on memory and modification of synaptic structure in hippocampus of adult mice were investigated in the present study. The adult mice were exposed to BPA (0.4, 4, and 40 mg/kg/day) or arachis oil for 12 weeks. In open field test, BPA at 0.4, 4, or 40 mg/kg/day increased the frequency of rearing and time in the central area of the males, while BPA at 0.4 mg/kg/day reduced the frequency of rearing in the females. Exposure to BPA (0.4 or 40 mg/kg/day) extended the average escape pathlength to the hidden platform in Morris water maze task and shortened the step-down latency 24 h after footshock of the males, but no changes were found in the females for these measures. Meanwhile, BPA induced a reduced numeric synaptic density and a negative effect on the structural parameters of synaptic interface, including an enlarged synaptic cleft and the reduced length of active zone and PSD thickness, in the hippocampus of the male mice. Western blot analyses further indicated that BPA down-regulated expressions of synaptic proteins (synapsin I and PSD-95) and synaptic NMDA receptor subunit NR1 and AMPA receptor subunit GluR1 in the hippocampus of the males. These results suggest that long-term exposure to low levels of BPA in adulthood sex-specifically impaired spatial and passive avoidance memory of mice. These effects may be associated with the higher susceptibility of the hippocampal synaptic plasticity processes, such as remodeling of spinal synapses and the expressions of synaptic proteins (e.g. synapsin I and PSD-95) and NMDA and AMPA receptors, to BPA in the adult male mice.
Collapse
Affiliation(s)
- Xiaohong Xu
- Chemistry and Life Sciences College, Zhejiang Normal University, PR China.
| | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Xu X, Xie L, Hong X, Ruan Q, Lu H, Zhang Q, Zhang G, Liu X. Perinatal exposure to bisphenol-A inhibits synaptogenesis and affects the synaptic morphological development in offspring male mice. CHEMOSPHERE 2013; 91:1073-1081. [PMID: 23490186 DOI: 10.1016/j.chemosphere.2012.12.065] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Revised: 12/18/2012] [Accepted: 12/21/2012] [Indexed: 06/01/2023]
Abstract
Our previous study indicated that perinatal exposure to low-dose BPA, one of the most common environmental endocrine disrupters, alters behavioral development in offspring mice. Given that synaptic structure of the hippocampus is closely related to behaviors, in the present study, we examined the effects of perinatal exposure to BPA (0.04, 0.4, and 4.0 mg kg(-1) day(-1)) on the synaptic density and the synaptic structural modification of pyramidal cells in hippocampus region CA1 and the expressions of synaptic proteins such as synapsin I and PSD-95 and glutamate NMDA and AMPA receptors in male offspring mice on postnatal day (PND) 14, 21, and 56. The results of electron microscope measurement showed that BPA significantly reduced the numeric synaptic density and altered the structural modification of synaptic interface of pyramidal cells with the enlarged synaptic cleft, the shortened active zone, and the thinned postsynaptic density (PSD) on PND 14, 21, and 56 and the increased curvature of synaptic interface on PND 14 and 21. Further analyses of Western blot indicated that BPA markedly reduced the levels of synapsin I and PSD-95 on PND 14, 21, and 56 and down-regulated NMDA receptor subunit NR1 and AMPA receptor subunit GluR1 during development and young adulthood. These results suggest that perinatal exposure to low level of BPA inhibits synaptogenesis and affects synaptic structural modification after birth. The reduced expressions of synaptic proteins synapsin I and PSD-95 and glutamate NMDA and AMPA receptors may be involved in the negative changes in the synaptic plasticity.
Collapse
Affiliation(s)
- Xiaohong Xu
- Chemistry and Life Science College, Zhejiang Normal University, Jinhua 321004, China.
| | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Di G, Zheng Y. Effects of high-speed railway noise on the synaptic ultrastructure and phosphorylated-CaMKII expression in the central nervous system of SD rats. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2013; 35:93-99. [PMID: 23274175 DOI: 10.1016/j.etap.2012.11.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Revised: 11/19/2012] [Accepted: 11/25/2012] [Indexed: 06/01/2023]
Abstract
To investigate the toxic effects of high-speed railway noise on learning and memory function, Sprague-Dawley (SD) rats were exposed to high-speed railway noise for 90 days. The noise was recorded from an actual environment and adjusted to a day-night equivalent continuous A-weighted sound pressure level (L(dn)) of 70dB(A). Transmission electron microscopy (TEM) and Western blot analysis were used to observe the synaptic ultrastructure and detect the level of phosphorylated-Ca(2+)/calmodulin-dependent protein kinase II (p-CaMKII), respectively, in the hippocampus, temporal lobe and amygdala. Compared with the sham control group, the results of the TEM showed that the width of the noise model group's synaptic cleft increased markedly in the hippocampus, amygdala (P<0.05) and temporal lobe (P<0.01); the thickness of postsynaptic density (PSD) decreased significantly (P<0.01). The results of the TEM suggest that the synaptic plasticity of structure and function were abnormal and that this abnormality resulted in a reduction in synaptic transmission efficiency. This reduction may have led to dysfunctions in learning and memory. Additionally, the Western blot analyses revealed that the level of p-CaMKII decreased significantly in the temporal lobe of the noise model group compared with the sham control group (P<0.05). The results of the Western blot analysis indicate a reduction in synaptic transmission efficiency, which resulted in impairments in learning and memory function in the temporal lobe. Both of the above conclusions are consistent with each other.
Collapse
Affiliation(s)
- Guoqing Di
- Institute of Environmental Pollution & Control Technology, Nongshenghuan Building B388, Zijingang Campus, Zhejiang University, Yuhangtang Road 866, Hangzhou, Zhejiang Province, China.
| | | |
Collapse
|
|
43
|
Henderson CN. The basis for spinal manipulation: Chiropractic perspective of indications and theory. J Electromyogr Kinesiol 2012; 22:632-42. [DOI: 10.1016/j.jelekin.2012.03.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2011] [Revised: 03/15/2012] [Accepted: 03/20/2012] [Indexed: 12/21/2022] Open
|
|
44
|
Armstrong BC, Le Boutillier JC, Petit TL. Ultrastructural synaptic changes associated with neurofibromatosis type 1: a quantitative analysis of hippocampal region CA1 in a Nf1(+/-) mouse model. Synapse 2011; 66:246-55. [PMID: 22121000 DOI: 10.1002/syn.21507] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2011] [Revised: 10/28/2011] [Accepted: 11/02/2011] [Indexed: 11/06/2022]
Abstract
Neurofibromatosis type 1 (NF1) is one of the most frequently diagnosed autosomal dominant inherited disorders resulting in neurological dysfunction, including an assortment of learning disabilities and cognitive deficits. To elucidate the neural mechanisms underlying the disorder, we employed a mouse model (Nf1(+/-) ) to conduct a quantitative analysis of ultrastructural changes associated with the NF1 disorder. Using both serial light and electron microscopy, we examined reconstructions of the CA1 region of the hippocampus, which is known to play a central role in many of the dysfunctions associated with NF1. In general, the morphology of synapses in both the Nf1(+/-) and wild-type groups of animals were similar. No differences were observed in synapse per neuron density, pre- and postsynaptic areas, or lengths. However, concave synapses were found to show a lower degree of curvature in the Nf1(+/-) mutant than in the wild type. These results indicate that the synaptic ultrastructure of Nf1(+/-) mice appears relatively normal with the exception of the degree of synaptic curvature in concave synapses, adding further support to the importance of synaptic curvature in synaptic plasticity, learning, and memory.
Collapse
Affiliation(s)
- Blair C Armstrong
- Department of Psychology and Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA
| | | | | |
Collapse
|
|
45
|
Lo FS, Zhao S, Erzurumlu RS. Astrocytes promote peripheral nerve injury-induced reactive synaptogenesis in the neonatal CNS. J Neurophysiol 2011; 106:2876-87. [PMID: 21900512 DOI: 10.1152/jn.00312.2011] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Neonatal damage to the trigeminal nerve leads to "reactive synaptogenesis" in the brain stem sensory trigeminal nuclei. In vitro models of brain injury-induced synaptogenesis have implicated an important role for astrocytes. In this study we tested the role of astrocyte function in reactive synaptogenesis in the trigeminal principal nucleus (PrV) of neonatal rats following unilateral transection of the infraorbital (IO) branch of the trigeminal nerve. We used electrophysiological multiple input index analysis (MII) to estimate the number of central trigeminal afferent fibers that converge onto single barrelette neurons. In the developing PrV, about 30% of afferent connections are eliminated within 2 postnatal weeks. After neonatal IO nerve damage, multiple trigeminal inputs (2.7 times that of the normal inputs) converge on single barrelette cells within 3-5 days; they remain stable up to the second postnatal week. Astrocyte proliferation and upregulation of astrocyte-specific proteins (GFAP and ALDH1L1) accompany reactive synaptogenesis in the IO nerve projection zone of the PrV. Pharmacological blockade of astrocyte function, purinergic receptors, and thrombospondins significantly reduced or eliminated reactive synaptogenesis without changing the MII in the intact PrV. GFAP immunohistochemistry further supported these electrophysiological results. We conclude that immature astrocytes, purinergic receptors, and thrombospondins play an important role in reactive synaptogenesis in the peripherally deafferented neonatal PrV.
Collapse
Affiliation(s)
- Fu-Sun Lo
- Department of Anatomy and Neurobiology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA
| | | | | |
Collapse
|
|
46
|
Medvedev NI, Popov VI, Dallérac G, Davies HA, Laroche S, Kraev IV, Rodriguez Arellano JJ, Doyère V, Stewart MG. Alterations in synaptic curvature in the dentate gyrus following induction of long-term potentiation, long-term depression, and treatment with the N-methyl-D-aspartate receptor antagonist CPP. Neuroscience 2010; 171:390-7. [PMID: 20849931 DOI: 10.1016/j.neuroscience.2010.09.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2010] [Revised: 09/04/2010] [Accepted: 09/08/2010] [Indexed: 10/19/2022]
Abstract
Alterations in curvature of the post synaptic density (PSD) and apposition zone (AZ), are believed to play an important role in determining synaptic efficacy. In the present study we have examined curvature of PSDs and AZs 24 h following homosynaptic long-term potentiation (LTP), and heterosynaptic long-term depression (LTD) in vivo, in awake adult rats. High frequency stimulation (HFS) applied to the medial perforant path to the dentate gyrus induced LTP while HFS stimulation of the lateral perforant path induced LTD in the middle molecular layer of the dentate gyrus (DG). Curvature changes were analysed in this area using three dimensional (3-D) reconstructions of electron microscope images of ultrathin serial sections. Very large and significant changes in 3-D measurements of AZ and PSD curvature occurred 24 h following both LTP and LTD, with a flattening of the normal concavity of mushroom spine heads and a change to convexity for thin spines. An N-methyl-D-aspartate (NMDA) receptor antagonist CPP (3-[(R)-2-Carboxypiperazin-4-yl]-propyl-1-phosphonic acid) blocked the changes in curvature of mushroom and thin spine PSDs and apposition zones, actually increasing the concavity of mushroom spines as the spine engulfed the presynaptic bouton. In order to establish whether these changes resulted from the effect of the NMDA antagonist or from its coincidence with synaptic activation during testing we examined the effects of CPP alone on PSD and apposition zone curvature. It was found that CPP alone also caused a small decrease in curvature of both PSD and apposition zone of mushroom and thin spines.
Collapse
Affiliation(s)
- N I Medvedev
- Department of Life Sciences, The Open University, Milton Keynes, UK
| | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Ginsberg SD. Alterations in discrete glutamate receptor subunits in adult mouse dentate gyrus granule cells following perforant path transection. Anal Bioanal Chem 2010; 397:3349-58. [PMID: 20577723 DOI: 10.1007/s00216-010-3826-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2010] [Revised: 04/27/2010] [Accepted: 05/04/2010] [Indexed: 01/25/2023]
Abstract
Custom-designed microarray analysis was utilized to evaluate expression levels of glutamate receptors (GluRs) and GluR-interacting protein genes within isolated dentate gyrus granule cells following axotomy of the principal input, the perforant path (PP). Dentate gyrus granule cells were evaluated by microdissection via laser capture microdissection, terminal continuation RNA amplification, and microarray analysis following unilateral PP transections at seven time points. Expression profiles garnered from granule cells on the side ipsilateral to PP transections were compared and contrasted with naive subjects and mice subjected to unilateral occipital cortex lesions. Selected microarray observations were validated by real-time quantitative PCR analysis. Postlesion time-dependent alterations in specific alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, kainate receptors, N-methyl-D-aspartate (NMDA) receptors, and GluR-interacting protein genes were found across the time course of the study, suggesting a neuroplasticity response associated with the transsynaptic granule cell alterations following axotomy of incoming PP terminals.
Collapse
Affiliation(s)
- Stephen D Ginsberg
- Department of Psychiatry, Center for Dementia Research, Nathan Kline Institute, New York University Langone Medical Center, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
| |
Collapse
|
|
48
|
Dahlhaus R, Hines RM, Eadie BD, Kannangara TS, Hines DJ, Brown CE, Christie BR, El-Husseini A. Overexpression of the cell adhesion protein neuroligin-1 induces learning deficits and impairs synaptic plasticity by altering the ratio of excitation to inhibition in the hippocampus. Hippocampus 2010; 20:305-22. [PMID: 19437420 DOI: 10.1002/hipo.20630] [Citation(s) in RCA: 110] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Trans-synaptic cell-adhesion molecules have been implicated in regulating CNS synaptogenesis. Among these, the Neuroligin (NL) family (NLs 1-4) of postsynaptic adhesion proteins has been shown to promote the development and specification of excitatory versus inhibitory synapses. NLs form a heterophilic complex with the presynaptic transmembrane protein Neurexin (NRX). A differential association of NLs with postsynaptic scaffolding proteins and NRX isoforms has been suggested to regulate the ratio of excitatory to inhibitory synapses (E/I ratio). Using transgenic mice, we have tested this hypothesis by overexpressing NL1 in vivo to determine whether the relative levels of these cell adhesion molecules may influence synapse maturation, long-term potentiation (LTP), and/or learning. We found that NL1-overexpressing mice show significant deficits in memory acquisition, but not in memory retrieval. Golgi and electron microscopy analysis revealed changes in synapse morphology indicative of increased maturation of excitatory synapses. In parallel, electrophysiological examination indicated a shift in the synaptic activity toward increased excitation as well as impairment in LTP induction. Our results demonstrate that altered balance in the expression of molecules necessary for synapse specification and development (such as NL1) can lead to defects in memory formation and synaptic plasticity and outline the importance of rigidly controlled synaptic maturation processes.
Collapse
Affiliation(s)
- Regina Dahlhaus
- Department of Psychiatry, University of British Columbia, Vancouver, BC
| | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Stewart M, Popov V, Medvedev N, Gabbott P, Corbett N, Kraev I, Davies H. Dendritic spine and synapse morphological alterations induced by a neural cell adhesion molecule mimetic. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2010; 663:373-83. [PMID: 20017034 DOI: 10.1007/978-1-4419-1170-4_23] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Michael Stewart
- Department of Life Sciences, Faculty of Sciences, The Open University, Walton Hall, Milton Keynes, MK76AA, UK.
| | | | | | | | | | | | | |
Collapse
|
|
50
|
Li M, Cui Z, Niu Y, Liu B, Fan W, Yu D, Deng J. Synaptogenesis in the developing mouse visual cortex. Brain Res Bull 2010; 81:107-13. [DOI: 10.1016/j.brainresbull.2009.08.028] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2009] [Revised: 08/18/2009] [Accepted: 08/18/2009] [Indexed: 01/05/2023]
|