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Myrou AD, Spilioti MG, Tsolaki AC, Frontistis AN, Savopoulos CG. Gamma-aminobutiric acid-B receptor antibody-related limbic encephalitis due to small cell lung carcinoma: Two case reports. World J Clin Cases 2025; 13:97716. [DOI: 10.12998/wjcc.v13.i16.97716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 09/04/2024] [Accepted: 09/23/2024] [Indexed: 02/10/2025] Open
Abstract
BACKGROUND Paraneoplastic limbic encephalitis (LE) is an inflammatory condition that affects the limbic system, cerebellum, and peripheral nervous system. It causes a range of symptoms including short-term memory loss, impaired cognitive function, behavioral and psychological disorders, and seizures. Paraneoplastic LE can occur when an immune response is activated due to antibodies targeting gamma-aminobutyric acid (GABA) B receptor (GABABR) interacting with antigens on tumor cells and the nervous system, resulting in tumors primarily as small cell lung carcinoma (SCLC).
CASE SUMMARY We discuss two cases of GABABR antibody-related LE resulting from SCLC. The patients’ symptoms were managed with immunotherapy but ended in premature death due to chemotherapy-related complications.
CONCLUSION Paraneoplastic syndrome is a notable cause of LE. Early intravenous immunoglobulin therapy may lead to temporary remission.
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Affiliation(s)
- Athena D Myrou
- Department of Internal Medicine, AHEPA University General Hospital, Thessaloniki 54636, Greece
| | - Martha G Spilioti
- Department of Neurology, AHEPA University General Hospital, Thessaloniki 54636, Greece
| | - Anthoula C Tsolaki
- Department of Neurology, AHEPA University General Hospital, Thessaloniki 54636, Greece
| | - Antonis N Frontistis
- Department of Neurology, AHEPA University General Hospital, Thessaloniki 54636, Greece
| | - Christos G Savopoulos
- Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki 54636, Greece
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Kajita Y, Ono K, Kaneda S, Mushiake H. Pterostilben upregulates GAD67-mediated GABA synthesis in hippocampal parvalbumin-positive cells. Neuroscience 2025; 573:482-490. [PMID: 40189131 DOI: 10.1016/j.neuroscience.2025.03.060] [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: 01/29/2025] [Revised: 02/21/2025] [Accepted: 03/25/2025] [Indexed: 04/12/2025]
Abstract
BACKGROUND AND PURPOSE Pterostilbene (PTE, 3,5-dimethoxy-4'-hydroxystilbene) is a naturally occurring polyphenol which has antiepileptic properties, and can be utilized as a prophylaxis in patients with seizures and who are at risk of developing epilepsy. However, the effects of PTE on the gamma-aminobutyric acid (GABA)-mediated (GABAergic) nervous system are poorly understood. This study aimed to evaluate the effects of PTE on the GABAergic neurons. EXPERIMENTAL APPROACH Male Long-Evans rats were orally administered PTE (200 mg/kg, 5 % Tween 80 in saline) for 10 days using a plastic sonde. The control group was treated with 5 % Tween 80 in saline in a similar manner. Approximately 24 h after the last treatment, we fixed and removed the brains and examined GABA, GAD67, and GAD65 expression in the hippocampal layers using immunohistochemical analysis. In addition, changed GAD expression was compared between the two main GABAergic subtypes, PV+ and SOM+ cells. KEY RESULTS We demonstrated that PTE treatment increased GABA expression in the hippocampus. These effects can be attributed to GAD67-mediated GABA synthesis in the PV+ cells. CONCLUSIONS AND IMPLICATIONS Our results uncovered that PTE increased GABA synthesis, suggesting that PTE has potential as a prophylactic drug for patients at risk of developing epilepsy.
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Affiliation(s)
- Yuki Kajita
- Department of Physiology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aobaku, Sendai 980-8575, Japan.
| | - Ko Ono
- Department of Physiology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aobaku, Sendai 980-8575, Japan
| | - Saya Kaneda
- Department of Physiology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aobaku, Sendai 980-8575, Japan
| | - Hajime Mushiake
- Department of Physiology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aobaku, Sendai 980-8575, Japan
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Zhang YT, Yang Y, Bu DP, Ma L. The effects of gamma-aminobutyric acid on growth performance, diarrhoea, ruminal fermentation, and antioxidant capacity in pre-weaned calves. Animal 2025; 19:101493. [PMID: 40279853 DOI: 10.1016/j.animal.2025.101493] [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: 09/11/2024] [Revised: 03/12/2025] [Accepted: 03/13/2025] [Indexed: 04/29/2025] Open
Abstract
The pre-weaning phase is a vital period for the growth and development of calves, significantly impacting their future health and productivity. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the mammalian central nervous system that lowers blood pressure, stimulates feed intake, and enhances antioxidant capability. Gamma-aminobutyric acid has been proven beneficial for adult cows, while little research has been conducted on calves. Therefore, this study examined the effects of GABA on growth performance, diarrhoea, ruminal fermentation, and antioxidant capacity in pre-weaned Holstein calves. Ninety male Holstein calves were allocated to five groups: 0 mg/d (G0), 25 mg/d (G25), 50 mg/d (G50), 100 mg/d (G100), and 200 mg/d (G200). The experiment was conducted from 11 to 75 days of calves age, and the calves were weaned at 75 days of age. Growth performance indicators, ruminal fluid, faecal score, and serum were collected at 11, 28, 42, 60, and 75 days of calves' age. The results showed that adding GABA positively affected average daily gain and body height, with no effects on diarrhoea frequency. All dosages significantly reduced acetate and total volatile fatty acid levels in ruminal fermentation, with butyrate showing a complex response at higher doses. Overall, we recommended 100 mg/d as the optimal GABA supplementation level to improve growth performance and regulate the ruminal fermentation of pre-weaned calves before weaning.
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Affiliation(s)
- Y T Zhang
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
| | - Y Yang
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
| | - D P Bu
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China; Joint Laboratory on Integrated Crop-Tree-Livestock Systems, Chinese Academy of Agricultural Sciences (CAAS), Ethiopian Institute of Agricultural Research (EIAR), and World Agroforestry Center (ICRAF), Beijing 100193, China
| | - L Ma
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China.
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Dow CT. Proposing Bromo-Epi-Androsterone (BEA) for Stiff Person Syndrome (SPS). Microorganisms 2025; 13:824. [PMID: 40284660 PMCID: PMC12029804 DOI: 10.3390/microorganisms13040824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 03/23/2025] [Accepted: 03/24/2025] [Indexed: 04/29/2025] Open
Abstract
SPS is characterized by progressive spasmodic muscular rigidity. SPS is thought to be an autoimmune disease with a prominent feature of antibodies against glutamic acid decarboxylase (GAD). GAD is responsible for the enzymatic conversion of glutamic acid (glutamate) into the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Reduced GABA activity leads to increased excitability in the central nervous system, resulting in muscle rigidity and spasms characteristic of SPS. While SPS is rare, anti-GAD antibodies seen in SPS are also seen in the much more common autoimmune disease, type 1 diabetes (T1D). There is evolving research showing that the anti-GAD antibodies of T1D are produced in response to the presence of mycobacterial heat shock protein 65 (mHSP65), and the mHSP65 is produced in response to an occult infection by a bacterium, Mycobacterium avium subspecies Paratuberculosis (MAP). Humans are broadly exposed to MAP in food, water, and air. There are linear and conformational similarities between the epitopes of GAD and mHSP65. This article proposes that MAP is also an infectious trigger for SPS. Dehydroepiandrosterone (DHEA) is a principal component of the steroid metabolome; it plateaus in young adults and then steadily declines. Bromo-epi-androsterone (BEA) is a potent synthetic analog of DHEA; unlike DHEA, it is non-androgenic, non-anabolic, and an effective modulator of immune dysregulation. BEA is also an anti-infective agent and has been shown to benefit mycobacterial infections, including tuberculosis and leprosy. With the immune stabilizing capacity of BEA as well as its anti-mycobacterial properties, there is reason to believe that a randomized clinical trial with BEA may be beneficial for SPS.
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Affiliation(s)
- Coad Thomas Dow
- McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA;
- Protibea Therapeutics, LLC., Naples, FL 34105, USA
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Demircubuk I, Candar E, Sengul G. Anatomical and neurochemical organization of the dorsal, lumbar precerebellar and sacral precerebellar nuclei in the human spinal cord. Ann Anat 2025; 259:152390. [PMID: 39938757 DOI: 10.1016/j.aanat.2025.152390] [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: 07/02/2024] [Revised: 01/19/2025] [Accepted: 02/06/2025] [Indexed: 02/14/2025]
Abstract
BACKGROUND AND PURPOSE The dorsal nucleus (Clarke's nucleus, D), lumbar precerebellar nucleus (LPrCb), and sacral precerebellar nucleus (Stilling's sacral nucleus, SPrCb) are precerebellar nuclei of the spinal cord. This study investigates the cytoarchitecture and neurochemical organization of the D, LPrCb, and SPrCb nuclei in the human spinal cord. MATERIAL AND METHODS Using Nissl staining and immunohistochemistry for markers including calbindin (Cb), calretinin (Cr), parvalbumin (Pv), choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD 65/67), and vesicular glutamate transporter 1 (VGLUT1), we analyzed sections from T1-T12, L1-L5, and S1-Co1 segments of a human spinal cord. RESULTS Our findings reveal a diverse range of neuron sizes and morphologies within these nuclei, with multipolar neurons being predominant. The immunohistochemical analysis showed distinct neurochemical characteristics, with varying densities of the markers across the D, LPrCb, and SPrCb. CONCLUSION This study provides the first detailed characterization of these nuclei in the human spinal cord, highlighting their intricate organization and suggesting potential functional similarities. The comprehensive understanding of the neurochemical profiles of these nuclei lays the groundwork for future research into their roles in motor coordination and their involvement in neurodegenerative diseases. Our findings underscore the importance of further investigation into the pathological changes occurring within the precerebellar nuclei to advance treatment and prevention strategies for related neurological disorders.
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Affiliation(s)
- Ibrahim Demircubuk
- Department of Anatomy, Institute of Health Sciences, Ege University, Izmir, Turkiye
| | - Esra Candar
- Department of Neuroscience, Institute of Health Sciences, Ege University, Izmir, Turkiye
| | - Gulgun Sengul
- Department of Anatomy, Institute of Health Sciences, Ege University, Izmir, Turkiye; Department of Anatomy School of Medicine, Ege University, Izmir, Turkiye.
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Cardellicchio P, Borgomaneri S. Level of M1 GABAB predicts micro offline consolidation of motor learning during wakefulness. NPJ SCIENCE OF LEARNING 2025; 10:10. [PMID: 39988595 PMCID: PMC11847931 DOI: 10.1038/s41539-025-00299-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 01/21/2025] [Indexed: 02/25/2025]
Abstract
The consolidation process stabilizes a new initially labile memory. This consolidation could operate on a shorter timescale during wakefulness after initial motor learning. Within micro-offline learning states, sequences of simple individual actions learned through interleaved practice are condensed into a unified skill through a time-dependent consolidation process occurring during wakeful periods. While emerging evidence links Glutamate and GABA modulations in the primary motor cortex (M1) to motor learning, its relationship with micro-offline consolidation processes in brief resting states during motor learning is unclear. To investigate this issue, we employed Transcranial magnetic stimulation (TMS) to evaluate whether interindividual variation of different neurotransmitters at rest influences motor learning consolidation in humans. Our results point to the role of GABAB in micro-offline motor consolidation processes during motor learning in M1. This finding could have an important impact on planning neuropharmacology or non-invasive brain stimulation approaches in clinical domains, such as post-stroke rehabilitation.
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Affiliation(s)
- Pasquale Cardellicchio
- Physical Medicine and Rehabilitation Unit, IRCCS Istituto Giannina Gaslini, 16147, Genova, Italy.
| | - Sara Borgomaneri
- Center for Studies and Research in Cognitive Neuroscience, Department of Psychology "Renzo Canestrari", Cesena Campus, Alma Mater Studiorum Università di Bologna, 47521, Cesena, Italy
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Peng Z, Jia Q, Mao J, Luo X, Huang A, Zheng H, Jiang S, Ma Q, Ma C, Yi Q. Neurotransmitters crosstalk and regulation in the reward circuit of subjects with behavioral addiction. Front Psychiatry 2025; 15:1439727. [PMID: 39876994 PMCID: PMC11773674 DOI: 10.3389/fpsyt.2024.1439727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 12/26/2024] [Indexed: 01/31/2025] Open
Abstract
Behavioral addictive disorders (BADs) have become a significant societal challenge over time. The central feature of BADs is the loss of control over engaging in and continuing behaviors, even when facing negative consequences. The neurobiological underpinnings of BADs primarily involve impairments in the reward circuitry, encompassing the ventral tegmental area, nucleus accumbens in the ventral striatum, and prefrontal cortex. These brain regions form networks that communicate through neurotransmitter signaling, leading to neurobiological changes in individuals with behavioral addictions. While dopamine has long been associated with the reward process, recent research highlights the role of other key neurotransmitters like serotonin, glutamate, and endorphins in BADs' development. These neurotransmitters interact within the reward circuitry, creating potential targets for therapeutic intervention. This improved understanding of neurotransmitter systems provides a foundation for developing targeted treatments and helps clinicians select personalized therapeutic approaches.
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Affiliation(s)
- Zhenlei Peng
- Xinjiang Clinical Medical Research Center of Mental Health, The Psychological Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Qiyu Jia
- Department of Trauma Orthopedics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Junxiong Mao
- Xinjiang Clinical Medical Research Center of Mental Health, The Psychological Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xiao Luo
- Xinjiang Clinical Medical Research Center of Mental Health, The Psychological Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Anqi Huang
- Child Mental Health Research Center, Nanjing Brain Hospital, Clinical Teaching Hospital of Medical School, Nanjing University, Nanjing, China
| | - Hao Zheng
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Zhejiang, China
| | - Shijie Jiang
- Xinjiang Clinical Medical Research Center of Mental Health, The Psychological Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Qi Ma
- Xinjiang Clinical Medical Research Center of Mental Health, The Psychological Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Xinjiang Key Laboratory of Metabolic Disease, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Chuang Ma
- Department of Trauma Orthopedics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Qizhong Yi
- Xinjiang Clinical Medical Research Center of Mental Health, The Psychological Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
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Yang Y, Jiang H, Yang W, Wang H, Wang M, Li X, Huang P, Fang S, Hao W, Yang Y, Zhao F, He W. The IVIG treatment response in autoimmune polyendocrine syndromes type 2 with anti-GAD65 antibody-associated stiff person syndrome: a case report and literature review. Front Immunol 2025; 15:1471115. [PMID: 39840065 PMCID: PMC11746041 DOI: 10.3389/fimmu.2024.1471115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 12/12/2024] [Indexed: 01/23/2025] Open
Abstract
Autoimmune polyendocrine syndromes (APS) is a rare group of disorders caused by impaired function of multiple endocrine glands due to disruption of immune tolerance. Of which, type 2 (APS-2) is the most common. Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme for the synthesis of gamma-aminobutyric acid (GABA). Anti-GAD antibodies are associated with various neurological disorders, including stiff person syndrome (SPS). SPS is characterized by axial muscle stiffness, rigidity, and intermittent painful muscle spasms, with a prevalence of one to two in a million, making it an extremely rare neurological disorder. The comorbidity of APS-2 with SPS is even rarer. Most practicing neurologists encounter only one or two cases of APS-2 combined with anti-GAD65 antibody-associated SPS in their careers, resulting in underdiagnosis and undertreatment, leading to severe disability and suffering. This case report describes a young male who initially exhibited hair loss, vitiligo, and previously unreported eosinophilia. Before his diagnosis, he was admitted multiple times, with symptoms improving following the addition of intravenous immunoglobulin (IVIG) therapy to a poor treatment regimen. This paper aims to increase physicians' awareness of this condition, enhancing the likelihood of early diagnosis and treatment.
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Affiliation(s)
- Yulong Yang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional, Chinese Medicine, Hefei, Anhui, China
| | - Hailin Jiang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional, Chinese Medicine, Hefei, Anhui, China
| | - Wenming Yang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional, Chinese Medicine, Hefei, Anhui, China
- Key Laboratory of Xin’An Medicine, Ministry of Education Hefei, Anhui, China
- Center for Xin’an Medicine and Modernization of Traditional Chinese Medicine, Institute of Health and Medicine Hefei Comprehensive National Science Center, Hefei, Anhui, China
| | - Han Wang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional, Chinese Medicine, Hefei, Anhui, China
- Key Laboratory of Xin’An Medicine, Ministry of Education Hefei, Anhui, China
| | - Meixia Wang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional, Chinese Medicine, Hefei, Anhui, China
- Key Laboratory of Xin’An Medicine, Ministry of Education Hefei, Anhui, China
| | - Xiang Li
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional, Chinese Medicine, Hefei, Anhui, China
| | - Peng Huang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional, Chinese Medicine, Hefei, Anhui, China
| | - Shuzhen Fang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional, Chinese Medicine, Hefei, Anhui, China
| | - Wenjie Hao
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional, Chinese Medicine, Hefei, Anhui, China
| | - Yue Yang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional, Chinese Medicine, Hefei, Anhui, China
| | - Furong Zhao
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional, Chinese Medicine, Hefei, Anhui, China
| | - Wei He
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional, Chinese Medicine, Hefei, Anhui, China
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Patel HJ, Stollberg LS, Choi CH, Nitsche MA, Shah NJ, Binkofski F. A study of long-term GABA and high-energy phosphate alterations in the primary motor cortex using anodal tDCS and 1H/ 31P MR spectroscopy. Front Hum Neurosci 2024; 18:1461417. [PMID: 39734666 PMCID: PMC11672121 DOI: 10.3389/fnhum.2024.1461417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 12/02/2024] [Indexed: 12/31/2024] Open
Abstract
Introduction Anodal transcranial direct current stimulation (tDCS) has been reported to modulate gamma-aminobutyric acid levels and cerebral energy consumption in the brain. This study aims to investigate long-term GABA and cerebral energy modulation following anodal tDCS over the primary motor cortex. Method To assess GABA and energy level changes, proton and phosphorus magnetic resonance spectroscopy data were acquired before and after anodal or sham tDCS. In anodal stimulation, a 1 mA current was applied for 20 min, and the duration of ramping the current up/down at the start and end of the intervention was 10 s. In the sham-stimulation condition, the current was first ramped up over a period of 10 s, then immediately ramped down, and the condition was maintained for the next 20 min. Results The GABA concentration increased significantly following anodal stimulation in the first and second post-stimulation measurements. Likewise, both ATP/Pi and PCr/Pi ratios increased after anodal stimulation in the first and second post-stimulation measurements. Conclusion The approach employed in this study shows the feasibility of measuring long-term modulation of GABA and high-energy phosphates following anodal tDCS targeting the left M1, offering valuable insights into the mechanisms of neuroplasticity and energy metabolism, which may have implications for applications of this intervention in clinical populations.
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Affiliation(s)
- Harshal Jayeshkumar Patel
- Division of Clinical Cognitive Sciences, Department of Neurology, RWTH Aachen University Hospital, Aachen, Germany
| | - Lea-Sophie Stollberg
- Division of Clinical Cognitive Sciences, Department of Neurology, RWTH Aachen University Hospital, Aachen, Germany
| | - Chang-Hoon Choi
- Institute of Neuroscience and Medicine-4, Forschungszentrum Jülich GmbH, Jülich, Germany
| | - Michael A. Nitsche
- Leibniz Research Centre for Working Environment and Human Factors, Department of Psychology and Neurosciences, Dortmund, Germany
| | - N. Jon Shah
- Institute of Neuroscience and Medicine-4, Forschungszentrum Jülich GmbH, Jülich, Germany
- JARA-BRAIN-Translational Medicine, Jülich-Aachen-Research-Alliance (JARA), Aachen, Germany
- Department of Neurology, RWTH Aachen University Hospital, Aachen, Germany
- Institute of Neuroscience and Medicine-11, Forschungszentrum Juelich, Jülich, Germany
| | - Ferdinand Binkofski
- Division of Clinical Cognitive Sciences, Department of Neurology, RWTH Aachen University Hospital, Aachen, Germany
- Institute of Neuroscience and Medicine-4, Forschungszentrum Jülich GmbH, Jülich, Germany
- JARA-BRAIN-Translational Medicine, Jülich-Aachen-Research-Alliance (JARA), Aachen, Germany
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Cracknell RO, Tavassoli T, Field DT. High-dose Vitamin-B6 reduces sensory over-responsivity. J Psychopharmacol 2024; 38:1147-1156. [PMID: 39180365 PMCID: PMC11528956 DOI: 10.1177/02698811241271972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/26/2024]
Abstract
BACKGROUND Sensory reactivity differences are experienced by between 5% and 15% of the population, often taking the form of sensory over-responsivity (SOR), in which sensory stimuli are experienced as unusually intense and everyday function is affected. A potential mechanism underlying over-responsivity is an imbalance between neural excitation and inhibition in which inhibitory influences are relatively weakened. Therefore, interventions that boost neural inhibition or reduce neural excitation may reduce SOR; Vitamin-B6 is the coenzyme for the conversion of excitatory glutamate to inhibitory gamma-aminobutyric acid (GABA), and in animal models, it both increases the concentration of GABA and reduces glutamate. AIMS To discover whether taking a high dose of Vitamin-B6 reduces SOR and other aspects of sensory reactivity. METHODS We recruited 300 adults (249 females) from the general population who completed the Sensory Processing 3-Dimensions Scale (SP-3D) first at baseline, and again following randomisation to either 1 month's supplementation with 100 mg Vitamin-B6, or one of two control conditions (1000 µg Vitamin-B12 or placebo). To focus on individuals who experience SOR, we analysed the effects of supplementation only on individuals with high baseline SOR scores (above the 87th percentile). RESULTS In individuals with SOR at baseline, Vitamin-B6 selectively reduced SOR compared to both placebo and Vitamin-B12. We also found that Vitamin-B6 selectively reduced postural disorder in individuals with high scores on this subscale at baseline, but there were no effects on the four remaining SP-3D subscales. CONCLUSIONS Clinical trials and mechanistic studies should now be conducted in autism, attention deficit hyperactivity disorder and other groups with SOR.
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Affiliation(s)
- Rebekah O Cracknell
- School of Psychology and Clinical Language Sciences, The University of Reading, Reading, Berkshire, UK
| | - Teresa Tavassoli
- School of Psychology and Clinical Language Sciences, The University of Reading, Reading, Berkshire, UK
| | - David T Field
- School of Psychology and Clinical Language Sciences, The University of Reading, Reading, Berkshire, UK
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11
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Li H, Rodríguez-Nieto G, Chalavi S, Seer C, Mikkelsen M, Edden RAE, Swinnen SP. MRS-assessed brain GABA modulation in response to task performance and learning. BEHAVIORAL AND BRAIN FUNCTIONS : BBF 2024; 20:22. [PMID: 39217354 PMCID: PMC11366171 DOI: 10.1186/s12993-024-00248-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 08/16/2024] [Indexed: 09/04/2024]
Abstract
Gamma-aminobutyric acid (GABA), the most important inhibitory neurotransmitter in the human brain, has long been considered essential in human behavior in general and learning in particular. GABA concentration can be quantified using magnetic resonance spectroscopy (MRS). Using this technique, numerous studies have reported associations between baseline GABA levels and various human behaviors. However, regional GABA concentration is not fixed and may exhibit rapid modulation as a function of environmental factors. Hence, quantification of GABA levels at several time points during the performance of tasks can provide insights into the dynamics of GABA levels in distinct brain regions. This review reports on findings from studies using repeated measures (n = 41) examining the dynamic modulation of GABA levels in humans in response to various interventions in the perceptual, motor, and cognitive domains to explore associations between GABA modulation and human behavior. GABA levels in a specific brain area may increase or decrease during task performance or as a function of learning, depending on its precise involvement in the process under investigation. Here, we summarize the available evidence and derive two overarching hypotheses regarding the role of GABA modulation in performance and learning. Firstly, training-induced increases in GABA levels appear to be associated with an improved ability to differentiate minor perceptual differences during perceptual learning. This observation gives rise to the 'GABA increase for better neural distinctiveness hypothesis'. Secondly, converging evidence suggests that reducing GABA levels may play a beneficial role in effectively filtering perceptual noise, enhancing motor learning, and improving performance in visuomotor tasks. Additionally, some studies suggest that the reduction of GABA levels is related to better working memory and successful reinforcement learning. These observations inspire the 'GABA decrease to boost learning hypothesis', which states that decreasing neural inhibition through a reduction of GABA in dedicated brain areas facilitates human learning. Additionally, modulation of GABA levels is also observed after short-term physical exercise. Future work should elucidate which specific circumstances induce robust GABA modulation to enhance neuroplasticity and boost performance.
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Affiliation(s)
- Hong Li
- Movement Control and Neuroplasticity Research Group, Group Biomedical Sciences, KU Leuven, Leuven, Belgium
- Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium
| | - Geraldine Rodríguez-Nieto
- Movement Control and Neuroplasticity Research Group, Group Biomedical Sciences, KU Leuven, Leuven, Belgium
- Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium
| | - Sima Chalavi
- Movement Control and Neuroplasticity Research Group, Group Biomedical Sciences, KU Leuven, Leuven, Belgium
- Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium
| | - Caroline Seer
- Movement Control and Neuroplasticity Research Group, Group Biomedical Sciences, KU Leuven, Leuven, Belgium
- Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium
| | - Mark Mikkelsen
- Department of Radiology, Weill Cornell Medicine, New York, NY, USA
| | - Richard A E Edden
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA
| | - Stephan P Swinnen
- Movement Control and Neuroplasticity Research Group, Group Biomedical Sciences, KU Leuven, Leuven, Belgium.
- Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium.
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12
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Kajita Y, Fukuda Y, Kawamatsu R, Oyanagi T, Mushiake H. Pentylenetetrazole kindling induces dynamic changes in GAD65 expression in hippocampal somatostatin interneurons. Pharmacol Biochem Behav 2024; 239:173755. [PMID: 38527654 DOI: 10.1016/j.pbb.2024.173755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 03/01/2024] [Accepted: 03/22/2024] [Indexed: 03/27/2024]
Abstract
INTRODUCTION One of the mechanisms of epileptgenesis is impairment of inhibitory neural circuits. Several studies have compared neural changes among subtypes of gamma-aminobutyric acid-related (GABAergic) neurons after acquired epileptic seizure. However, it is unclear that GABAergic neural modifications that occur during acquisition process of epileptic seizure. METHODS Male rats were injected with pentylenetetrazole (PTZ kindling: n = 30) or saline (control: n = 15) every other day to observe the development of epileptic seizure stages. Two time points were identified: the point at which seizures were most difficult to induce, and the point at which seizures were most easy to induce. The expression of GABAergic neuron-related proteins in the hippocampus was immunohistochemically compared among GABAergic subtypes at each of these time points. RESULTS Bimodal changes in seizure stages were observed in response to PTZ kindling. The increase of seizure stage was transiently suppressed after 8 or 10 injections, and then progressed again by the 16th injection. Based on these results, we defined 10 injections as a short-term injection period during which seizures are less likely to occur, and 20 injections as a long-term injection period during which continuous seizures are likely to occur. The immunohistochemical analysis showed that hippocampal glutamic acid decarboxylase 65 (GAD65) expression was increased after short-term kindling but unchanged after long-term kindling. Increased GAD65 expression was limited to somatostatin-positive (SOM+) cells among several GABAergic subtypes. By contrast, GAD, GABA, GABAAR α1, GABABR1, and VGAT cells showed no change following short- or long-term PTZ kindling. CONCLUSION PTZ kindling induces bimodal changes in the epileptic seizure stage. Seizure stage is transiently suppressed after short-term PTZ injection with GAD65 upregulation in SOM+ cells. The seizure stage is progressed again after long-term PTZ injection with GAD65 reduction to baseline level.
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Affiliation(s)
- Yuki Kajita
- Department of Physiology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
| | - Yuki Fukuda
- Department of Physiology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Riho Kawamatsu
- Department of Physiology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Takanori Oyanagi
- Department of Physiology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Hajime Mushiake
- Department of Physiology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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13
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Braga JD, Thongngam M, Kumrungsee T. Gamma-aminobutyric acid as a potential postbiotic mediator in the gut-brain axis. NPJ Sci Food 2024; 8:16. [PMID: 38565567 PMCID: PMC10987602 DOI: 10.1038/s41538-024-00253-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 02/01/2024] [Indexed: 04/04/2024] Open
Abstract
Gamma-aminobutyric acid (GABA) plays a crucial role in the central nervous system as an inhibitory neurotransmitter. Imbalances of this neurotransmitter are associated with neurological diseases, such as Alzheimer's and Parkinson's disease, and psychological disorders, including anxiety, depression, and stress. Since GABA has long been believed to not cross the blood-brain barrier, the effects of circulating GABA on the brain are neglected. However, emerging evidence has demonstrated that changes in both circulating and brain levels of GABA are associated with changes in gut microbiota composition and that changes in GABA levels and microbiota composition play a role in modulating mental health. This recent research has raised the possibility that GABA may be a potent mediator of the gut-brain axis. This review article will cover up-to-date information about GABA-producing microorganisms isolated from human gut and food sources, explanation why those microorganisms produce GABA, food factors inducing gut-GABA production, evidence suggesting GABA as a mediator linking between gut microbiota and mental health, including anxiety, depression, stress, epilepsy, autism spectrum disorder, and attention deficit hyperactivity disorder, and novel information regarding homocarnosine-a predominant brain peptide that is a putative downstream mediator of GABA in regulating brain functions. This review will help us to understand how the gut microbiota and GABA-homocarnosine metabolism play a significant role in brain functions. Nonetheless, it could support further research on the use of GABA production-inducing microorganisms and food factors as agents to treat neurological and psychological disorders.
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Affiliation(s)
- Jason D Braga
- Laboratory of Molecular Nutrition, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, 739-8527, Japan
- Institute of Food Science and Technology, College of Agriculture, Food, Environment and Natural Resources, Cavite State University, Indang, Cavite, 4122, Philippines
| | - Masubon Thongngam
- Department of Food Science and Technology, Faculty of Agro-Industry, Kasetsart University, Bangkok, 10900, Thailand
| | - Thanutchaporn Kumrungsee
- Laboratory of Molecular Nutrition, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, 739-8527, Japan.
- Smart Agriculture, Graduate School of Innovation and Practice for Smart Society, Hiroshima University, Hiroshima, 739-8527, Japan.
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14
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Witkin JM, Shafique H, Cerne R, Smith JL, Marini AM, Lipsky RH, Delery E. Mechanistic and therapeutic relationships of traumatic brain injury and γ-amino-butyric acid (GABA). Pharmacol Ther 2024; 256:108609. [PMID: 38369062 DOI: 10.1016/j.pharmthera.2024.108609] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 01/18/2024] [Accepted: 02/01/2024] [Indexed: 02/20/2024]
Abstract
Traumatic brain injury (TBI) is a highly prevalent medical condition for which no medications specific for the prophylaxis or treatment of the condition as a whole exist. The spectrum of symptoms includes coma, headache, seizures, cognitive impairment, depression, and anxiety. Although it has been known for years that the inhibitory neurotransmitter γ-amino-butyric acid (GABA) is involved in TBI, no novel therapeutics based upon this mechanism have been introduced into clinical practice. We review the neuroanatomical, neurophysiological, neurochemical, and neuropharmacological relationships of GABA neurotransmission to TBI with a view toward new potential GABA-based medicines. The long-standing idea that excitatory and inhibitory (GABA and others) balances are disrupted by TBI is supported by the experimental data but has failed to invent novel methods of restoring this balance. The slow progress in advancing new treatments is due to the complexity of the disorder that encompasses multiple dynamically interacting biological processes including hemodynamic and metabolic systems, neurodegeneration and neurogenesis, major disruptions in neural networks and axons, frank brain lesions, and a multitude of symptoms that have differential neuronal and neurohormonal regulatory mechanisms. Although the current and ongoing clinical studies include GABAergic drugs, no novel GABA compounds are being explored. It is suggested that filling the gap in understanding the roles played by specific GABAA receptor configurations within specific neuronal circuits could help define new therapeutic approaches. Further research into the temporal and spatial delivery of GABA modulators should also be useful. Along with GABA modulation, research into the sequencing of GABA and non-GABA treatments will be needed.
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Affiliation(s)
- Jeffrey M Witkin
- Laboratory of Antiepileptic Drug Discovery, Ascension St. Vincent Hospital, Indianapolis, IN, USA; Departments of Neuroscience and Trauma Research, Ascension St. Vincent Hospital, Indianapolis, IN, USA; RespireRx Pharmaceuticals Inc, Glen Rock, NJ, USA.
| | | | - Rok Cerne
- Laboratory of Antiepileptic Drug Discovery, Ascension St. Vincent Hospital, Indianapolis, IN, USA; RespireRx Pharmaceuticals Inc, Glen Rock, NJ, USA; Department of Anatomy and Cell Biology, Indiana University/Purdue University, Indianapolis, IN, USA
| | - Jodi L Smith
- Laboratory of Antiepileptic Drug Discovery, Ascension St. Vincent Hospital, Indianapolis, IN, USA
| | - Ann M Marini
- Department of Neurology, Program in Neuroscience, and Molecular and Cellular Biology Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Robert H Lipsky
- Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Elizabeth Delery
- College of Osteopathic Medicine, Marian University, Indianapolis, IN, USA.
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15
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Gillespie B, Panthi S, Sundram S, Hill RA. The impact of maternal immune activation on GABAergic interneuron development: A systematic review of rodent studies and their translational implications. Neurosci Biobehav Rev 2024; 156:105488. [PMID: 38042358 DOI: 10.1016/j.neubiorev.2023.105488] [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: 08/11/2023] [Revised: 11/09/2023] [Accepted: 11/27/2023] [Indexed: 12/04/2023]
Abstract
Mothers exposed to infections during pregnancy disproportionally birth children who develop autism and schizophrenia, disorders associated with altered GABAergic function. The maternal immune activation (MIA) model recapitulates this risk factor, with many studies also reporting disruptions to GABAergic interneuron expression, protein, cellular density and function. However, it is unclear if there are species, sex, age, region, or GABAergic subtype specific vulnerabilities to MIA. Furthermore, to fully comprehend the impact of MIA on the GABAergic system a synthesised account of molecular, cellular, electrophysiological and behavioural findings was required. To this end we conducted a systematic review of GABAergic interneuron changes in the MIA model, focusing on the prefrontal cortex and hippocampus. We reviewed 102 articles that revealed robust changes in a number of GABAergic markers that present as gestationally-specific, region-specific and sometimes sex-specific. Disruptions to GABAergic markers coincided with distinct behavioural phenotypes, including memory, sensorimotor gating, anxiety, and sociability. Findings suggest the MIA model is a valid tool for testing novel therapeutics designed to recover GABAergic function and associated behaviour.
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Affiliation(s)
- Brendan Gillespie
- Department of Psychiatry, School of Clinical Sciences, Monash University, Clayton, VIC 3168, Australia
| | - Sandesh Panthi
- Department of Psychiatry, School of Clinical Sciences, Monash University, Clayton, VIC 3168, Australia
| | - Suresh Sundram
- Department of Psychiatry, School of Clinical Sciences, Monash University, Clayton, VIC 3168, Australia
| | - Rachel A Hill
- Department of Psychiatry, School of Clinical Sciences, Monash University, Clayton, VIC 3168, Australia.
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16
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Ryding M, Mikkelsen AW, Nissen MS, Nilsson AC, Blaabjerg M. Pathophysiological Effects of Autoantibodies in Autoimmune Encephalitides. Cells 2023; 13:15. [PMID: 38201219 PMCID: PMC10778077 DOI: 10.3390/cells13010015] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/15/2023] [Accepted: 12/18/2023] [Indexed: 01/12/2024] Open
Abstract
The heterogeneity of autoantibody targets in autoimmune encephalitides presents a challenge for understanding cellular and humoral pathophysiology, and the development of new treatment strategies. Thus, current treatment aims at autoantibody removal and immunosuppression, and is primarily based on data generated from other autoimmune neurological diseases and expert consensus. There are many subtypes of autoimmune encephalitides, which now entails both diseases with autoantibodies targeting extracellular antigens and classical paraneoplastic syndromes with autoantibodies targeting intracellular antigens. Here, we review the current knowledge of molecular and cellular effects of autoantibodies associated with autoimmune encephalitis, and evaluate the evidence behind the proposed pathophysiological mechanisms of autoantibodies in autoimmune encephalitis.
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Affiliation(s)
- Matias Ryding
- Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark;
- Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark
| | - Anne With Mikkelsen
- Department of Clinical Immunology, Odense University Hospital, 5000 Odense, Denmark;
| | | | - Anna Christine Nilsson
- Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark;
- Department of Clinical Immunology, Odense University Hospital, 5000 Odense, Denmark;
| | - Morten Blaabjerg
- Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark;
- Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark
- Department of Neurology, Odense University Hospital, 5000 Odense, Denmark;
- Brain Research—Inter Disciplinary Guided Excellence (BRIDGE), 5000 Odense, Denmark
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17
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Gorman-Sandler E, Wood G, Cloude N, Frambes N, Brennen H, Robertson B, Hollis F. Mitochondrial might: powering the peripartum for risk and resilience. Front Behav Neurosci 2023; 17:1286811. [PMID: 38187925 PMCID: PMC10767224 DOI: 10.3389/fnbeh.2023.1286811] [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: 09/01/2023] [Accepted: 11/01/2023] [Indexed: 01/09/2024] Open
Abstract
The peripartum period, characterized by dynamic hormonal shifts and physiological adaptations, has been recognized as a potentially vulnerable period for the development of mood disorders such as postpartum depression (PPD). Stress is a well-established risk factor for developing PPD and is known to modulate mitochondrial function. While primarily known for their role in energy production, mitochondria also influence processes such as stress regulation, steroid hormone synthesis, glucocorticoid response, GABA metabolism, and immune modulation - all of which are crucial for healthy pregnancy and relevant to PPD pathology. While mitochondrial function has been implicated in other psychiatric illnesses, its role in peripartum stress and mental health remains largely unexplored, especially in relation to the brain. In this review, we first provide an overview of mitochondrial involvement in processes implicated in peripartum mood disorders, underscoring their potential role in mediating pathology. We then discuss clinical and preclinical studies of mitochondria in the context of peripartum stress and mental health, emphasizing the need for better understanding of this relationship. Finally, we propose mitochondria as biological mediators of resilience to peripartum mood disorders.
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Affiliation(s)
- Erin Gorman-Sandler
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
- Columbia VA Healthcare System, Columbia, SC, United States
| | - Gabrielle Wood
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Nazharee Cloude
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Noelle Frambes
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Hannah Brennen
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Breanna Robertson
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Fiona Hollis
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
- Columbia VA Healthcare System, Columbia, SC, United States
- USC Institute for Cardiovascular Disease Research, Columbia, SC, United States
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18
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Koh W, Kwak H, Cheong E, Lee CJ. GABA tone regulation and its cognitive functions in the brain. Nat Rev Neurosci 2023; 24:523-539. [PMID: 37495761 DOI: 10.1038/s41583-023-00724-7] [Citation(s) in RCA: 76] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2023] [Indexed: 07/28/2023]
Abstract
γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter released at GABAergic synapses, mediating fast-acting phasic inhibition. Emerging lines of evidence unequivocally indicate that a small amount of extracellular GABA - GABA tone - exists in the brain and induces a tonic GABA current that controls neuronal activity on a slow timescale relative to that of phasic inhibition. Surprisingly, studies indicate that glial cells that synthesize GABA, such as astrocytes, release GABA through non-vesicular mechanisms, such as channel-mediated release, and thereby act as the source of GABA tone in the brain. In this Review, we first provide an overview of major advances in our understanding of the cell-specific molecular and cellular mechanisms of GABA synthesis, release and clearance that regulate GABA tone in various brain regions. We next examine the diverse ways in which the tonic GABA current regulates synaptic transmission and synaptic plasticity through extrasynaptic GABAA-receptor-mediated mechanisms. Last, we discuss the physiological mechanisms through which tonic inhibition modulates cognitive function on a slow timescale. In this Review, we emphasize that the cognitive functions of tonic GABA current extend beyond mere inhibition, laying a foundation for future research on the physiological and pathophysiological roles of GABA tone regulation in normal and abnormal psychiatric conditions.
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Affiliation(s)
- Wuhyun Koh
- Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea
| | - Hankyul Kwak
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Eunji Cheong
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
| | - C Justin Lee
- Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea.
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19
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Dowling KF, Dienel SJ, Barile Z, Bazmi HH, Lewis DA. Localization and Diagnostic Specificity of Glutamic Acid Decarboxylase Transcript Alterations in the Dorsolateral Prefrontal Cortex in Schizophrenia. Biol Psychiatry 2023; 94:322-331. [PMID: 37061080 PMCID: PMC10524522 DOI: 10.1016/j.biopsych.2023.04.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/24/2023] [Accepted: 04/03/2023] [Indexed: 04/17/2023]
Abstract
BACKGROUND Working memory (WM) deficits in schizophrenia are thought to reflect altered inhibition in the dorsolateral prefrontal cortex (DLPFC). This interpretation is supported by findings of lower transcript levels of the 2 enzymes, GAD67 and GAD65, which mediate basal and activity-dependent GABA (gamma-aminobutyric acid) synthesis, respectively. However, the relative magnitude, location within the depth of the DLPFC, and specificity to the disease process of schizophrenia of alterations in GAD67 and/or GAD65 remain unclear. METHODS Levels of GAD67 and GAD65 messenger RNAs (mRNAs) in superficial (layers 2/superficial 3) and deep (deep layer 6/white matter) zones of the DLPFC were quantified by quantitative polymerase chain reaction in subjects with schizophrenia (n = 41), major depression (n = 42), or bipolar disorder (n = 39) and unaffected comparison (n = 43) subjects. RESULTS Relative to the unaffected comparison group, GAD67 and GAD65 mRNA levels in the schizophrenia group were lower (p = .039, effect size = -0.69 and p = .027, effect size = -0.72, respectively) in the superficial zone but were unaltered in the deep zone. In the major depression group, only GAD67 mRNA levels were lower and only in the superficial zone (p = .089, effect size = 0.70). No differences were detected in the bipolar disorder group. Neither GAD67 nor GAD65 mRNA alterations were explained by psychosis, mood disturbance, or common comorbid factors. CONCLUSIONS Alterations in markers of GABA synthesis demonstrated transcript, DLPFC zone, and diagnostic specificity. Given the dependence of WM on GABA neurotransmission in the superficial DLPFC, our findings suggest that limitations to GABA synthesis in this location contribute to WM impairments in schizophrenia, especially during demanding WM tasks, when GABA synthesis requires the activity of both GAD67 and GAD65.
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Affiliation(s)
- Kevin F Dowling
- Medical Scientist Training Program, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Neuroscience, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Samuel J Dienel
- Medical Scientist Training Program, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Neuroscience, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania
| | - Zackery Barile
- Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - H Holly Bazmi
- Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - David A Lewis
- Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Neuroscience, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania.
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Paparella I, Vanderwalle G, Stagg CJ, Maquet P. An integrated measure of GABA to characterize post-stroke plasticity. Neuroimage Clin 2023; 39:103463. [PMID: 37406594 PMCID: PMC10339061 DOI: 10.1016/j.nicl.2023.103463] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 06/19/2023] [Accepted: 06/24/2023] [Indexed: 07/07/2023]
Abstract
Stroke is a major cause of death and chronic neurological disability. Despite the improvements in stroke care, the number of patients affected by stroke keeps increasing and many stroke survivors are left permanently disabled. Current therapies are limited in efficacy. Understanding the neurobiological mechanisms underlying post-stroke recovery is therefore crucial to find new therapeutic options to address this medical burden. Long-lasting and widespread alterations of γ-aminobutyric acid (GABA) neurotransmission seem to play a key role in stroke recovery. In this review we first discuss a possible model of GABAergic modulation of post-stroke plasticity. We then overview the techniques currently available to non-invasively assess GABA in patients and the conclusions drawn from this limited body of work. Finally, we address the remaining open questions to clarify GABAergic changes underlying post-stroke recovery, we briefly review possible ways to modulate GABA post stroke and propose a novel approach to thoroughly quantify GABA in stroke patients, by integrating its concentration, the activity of its receptors and its link with microstructural changes.
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Affiliation(s)
- Ilenia Paparella
- GIGA-Research, Cyclotron Research Center-In Vivo Imaging Unit, 8 allée du Six Août, Batiment B30, University of Liège, 4000 Liège, Belgium.
| | - Gilles Vanderwalle
- GIGA-Research, Cyclotron Research Center-In Vivo Imaging Unit, 8 allée du Six Août, Batiment B30, University of Liège, 4000 Liège, Belgium
| | - Charlotte J Stagg
- Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Medical Research Council Brain Network Dynamics Unit, Oxford, UK
| | - Pierre Maquet
- GIGA-Research, Cyclotron Research Center-In Vivo Imaging Unit, 8 allée du Six Août, Batiment B30, University of Liège, 4000 Liège, Belgium; Department of Neurology, Domaine Universitaire du Sart Tilman, Bâtiment B35, CHU de Liège, 4000 Liège, Belgium
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21
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Bach KT, Ananth S, Thind I, Zhong N, Lui F. Co-occurrence of Anti-GAD65 Syndrome, Type 1 Diabetes Mellitus, and Focal Seizures With Impaired Awareness. Cureus 2023; 15:e40611. [PMID: 37476109 PMCID: PMC10354376 DOI: 10.7759/cureus.40611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2023] [Indexed: 07/22/2023] Open
Abstract
Glutamic acid decarboxylase (GAD) is an intracellular enzyme found in the presynaptic end of nerve terminals that functions to synthesize gamma-aminobutyric acid (GABA) via decarboxylation. Autoantibodies to the GAD65 isoform have been found in high levels in neurological disorders including stiff person syndrome (SPS), autoimmune encephalitis, and refractory epilepsy. Low levels of anti-GAD65 have also been noted in type 1 diabetes mellitus. We present the unusual case of a woman with a longstanding history of focal seizures with impaired awareness and type 1 diabetes mellitus who was found to have extremely high titers of anti-GAD65 and clinical presentation suggestive of stiff person syndrome. This case highlights the increasing significance of autoimmune etiologies within neurologic disorders, as well as the importance of maintaining a high index of suspicion for rare anti-GAD65 syndromes. Although uncommon and with an unclear pathophysiology, we discuss the importance of establishing SPS diagnostic criteria to facilitate timely diagnosis and quickly direct patient management towards immunotherapy.
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Affiliation(s)
- Kieu-Tram Bach
- Clinical Sciences, California Northstate University College of Medicine, Sacramento, USA
| | - Shahini Ananth
- Clinical Sciences, California Northstate University College of Medicine, Sacramento, USA
| | - Ikjot Thind
- Clinical Sciences, California Northstate University College of Medicine, Sacramento, USA
| | - Ning Zhong
- Neurology, Kaiser Permanente Sacramento Medical Center, Sacramento, USA
| | - Forshing Lui
- Clinical Sciences, California Northstate University College of Medicine, Elk Grove, USA
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22
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Avila-Luna A, Gálvez-Rosas A, Aguirre-Pérez A, Hidalgo-Bravo A, Alfaro-Rodriguez A, Ríos C, Arias-Montaño JA, Bueno-Nava A. Chronic H 3R activation reduces L-Dopa-induced dyskinesia, normalizes cortical GABA and glutamate levels, and increases striatal dopamine D 1R mRNA expression in 6-hydroxydopamine-lesioned male rats. Psychopharmacology (Berl) 2023; 240:1221-1234. [PMID: 37086286 DOI: 10.1007/s00213-023-06339-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 02/09/2023] [Indexed: 04/23/2023]
Abstract
RATIONALE Dyskinesias induced by L-3,4-dihydroxyphenylalanine, L-Dopa (LIDs), are the major complication in the pharmacological treatment of Parkinson's disease. LIDs induce overactivity of the glutamatergic cortico-striatal projections, and drugs that reduce glutamatergic overactivity exert antidyskinetic actions. Chronic administration of immepip, agonist at histamine H3 receptors (H3R), reduces LIDs and diminishes GABA and glutamate content in striatal dialysates (Avila-Luna et al., Psychopharmacology 236: 1937-1948, 2019). OBJECTIVES AND METHODS In rats unilaterally lesioned with 6-hydroxydopamine in the substantia nigra pars compacta (SNc), we examined whether the chronic administration of immepip and their withdrawal modify LIDs, the effect of L-Dopa on glutamate and GABA content, and mRNA levels of dopamine D1 receptors (D1Rs) and H3Rs in the cerebral cortex and striatum. RESULTS The administration of L-Dopa for 21 days induced LIDs. This effect was accompanied by increased GABA and glutamate levels in the cerebral cortex ipsi and contralateral to the lesioned SNc, and immepip administration prevented (GABA) or reduced (glutamate) these actions. In the striatum, GABA content increased in the ipsilateral nucleus, an effect prevented by immepip. L-Dopa administration had no significant effects on striatal glutamate levels. In lesioned and L-Dopa-treated animals, D1R mRNA decreased in the ipsilateral striatum, an effect prevented by immepip administration. CONCLUSIONS Our results indicate that chronic H3R activation reduces LIDs and the overactivity of glutamatergic cortico-striatal projections, providing further evidence for an interaction between D1Rs and H3Rs in the cortex and striatum under normal and pathological conditions.
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Affiliation(s)
- Alberto Avila-Luna
- Coordinación de Neurociencias Básicas, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, SSa, Calzada México-Xochimilco 289, Arenal de Guadalupe, Ciudad de México, 14389, México
- Laboratorio de Neurofisiología Química de la Discapacidad, Coordinación de Neurociencias Básicas, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, SSa, Calz. México-Xochimilco 289, Arenal de Guadalupe, Ciudad de México, 14389, México
| | - Arturo Gálvez-Rosas
- Coordinación de Neurociencias Básicas, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, SSa, Calzada México-Xochimilco 289, Arenal de Guadalupe, Ciudad de México, 14389, México
- Laboratorio de Neurofisiología Química de la Discapacidad, Coordinación de Neurociencias Básicas, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, SSa, Calz. México-Xochimilco 289, Arenal de Guadalupe, Ciudad de México, 14389, México
| | - Alexander Aguirre-Pérez
- Laboratorio de Neurofisiología Química de la Discapacidad, Coordinación de Neurociencias Básicas, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, SSa, Calz. México-Xochimilco 289, Arenal de Guadalupe, Ciudad de México, 14389, México
| | - Alberto Hidalgo-Bravo
- Departamento de Medicina Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, SSa, Calzada México-Xochimilco 289, Arenal de Guadalupe, Ciudad de México, 14389, México
| | - Alfonso Alfaro-Rodriguez
- Coordinación de Neurociencias Básicas, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, SSa, Calzada México-Xochimilco 289, Arenal de Guadalupe, Ciudad de México, 14389, México
| | - Camilo Ríos
- Coordinación de Neurociencias Básicas, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, SSa, Calzada México-Xochimilco 289, Arenal de Guadalupe, Ciudad de México, 14389, México
- Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, SSa, Insurgentes Sur 3877, La Fama, Ciudad de México, 14269, México
- Laboratorio de Neurofarmacología Molecular, Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana, Unidad Xochimilco, Calzada del Hueso 1100, Col. Villa Quietud, Ciudad de México, 04960, México
| | - José-Antonio Arias-Montaño
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Av. IPN 2508, Zacatenco, Ciudad de México, 07360, México
| | - Antonio Bueno-Nava
- Coordinación de Neurociencias Básicas, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, SSa, Calzada México-Xochimilco 289, Arenal de Guadalupe, Ciudad de México, 14389, México.
- Laboratorio de Neurofisiología Química de la Discapacidad, Coordinación de Neurociencias Básicas, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, SSa, Calz. México-Xochimilco 289, Arenal de Guadalupe, Ciudad de México, 14389, México.
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23
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Huffels CFM, Middeldorp J, Hol EM. Aß Pathology and Neuron-Glia Interactions: A Synaptocentric View. Neurochem Res 2023; 48:1026-1046. [PMID: 35976488 PMCID: PMC10030451 DOI: 10.1007/s11064-022-03699-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 06/30/2022] [Accepted: 07/15/2022] [Indexed: 10/15/2022]
Abstract
Alzheimer's disease (AD) causes the majority of dementia cases worldwide. Early pathological hallmarks include the accumulation of amyloid-ß (Aß) and activation of both astrocytes and microglia. Neurons form the building blocks of the central nervous system, and astrocytes and microglia provide essential input for its healthy functioning. Their function integrates at the level of the synapse, which is therefore sometimes referred to as the "quad-partite synapse". Increasing evidence puts AD forward as a disease of the synapse, where pre- and postsynaptic processes, as well as astrocyte and microglia functioning progressively deteriorate. Here, we aim to review the current knowledge on how Aß accumulation functionally affects the individual components of the quad-partite synapse. We highlight a selection of processes that are essential to the healthy functioning of the neuronal synapse, including presynaptic neurotransmitter release and postsynaptic receptor functioning. We further discuss how Aß affects the astrocyte's capacity to recycle neurotransmitters, release gliotransmitters, and maintain ion homeostasis. We additionally review literature on how Aß changes the immunoprotective function of microglia during AD progression and conclude by summarizing our main findings and highlighting the challenges in current studies, as well as the need for further research.
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Affiliation(s)
- Christiaan F M Huffels
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
| | - Jinte Middeldorp
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
- Department of Neurobiology & Aging, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - Elly M Hol
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
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24
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Bang JW, Hamilton-Fletcher G, Chan KC. Visual Plasticity in Adulthood: Perspectives from Hebbian and Homeostatic Plasticity. Neuroscientist 2023; 29:117-138. [PMID: 34382456 PMCID: PMC9356772 DOI: 10.1177/10738584211037619] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The visual system retains profound plastic potential in adulthood. In the current review, we summarize the evidence of preserved plasticity in the adult visual system during visual perceptual learning as well as both monocular and binocular visual deprivation. In each condition, we discuss how such evidence reflects two major cellular mechanisms of plasticity: Hebbian and homeostatic processes. We focus on how these two mechanisms work together to shape plasticity in the visual system. In addition, we discuss how these two mechanisms could be further revealed in future studies investigating cross-modal plasticity in the visual system.
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Affiliation(s)
- Ji Won Bang
- Department of Ophthalmology, NYU Grossman School of Medicine, NYU Langone Health, New York University, New York, NY, USA
| | - Giles Hamilton-Fletcher
- Department of Ophthalmology, NYU Grossman School of Medicine, NYU Langone Health, New York University, New York, NY, USA
| | - Kevin C. Chan
- Department of Ophthalmology, NYU Grossman School of Medicine, NYU Langone Health, New York University, New York, NY, USA
- Department of Radiology, NYU Grossman School of Medicine, NYU Langone Health, New York University, New York, NY, USA
- Neuroscience Institute, NYU Grossman School of Medicine, NYU Langone Health, New York University, New York, NY, USA
- Center for Neural Science, College of Arts and Science, New York University, New York, NY, USA
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25
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The Anti-Seizure Effect of Liraglutide on Ptz-Induced Convulsions Through its Anti-Oxidant and Anti-Inflammatory Properties. Neurochem Res 2023; 48:188-195. [PMID: 36040609 DOI: 10.1007/s11064-022-03736-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 01/11/2023]
Abstract
Epilepsy is a prevalent and frequently devastating neurological disorder defined by recurring spontaneous seizures caused by aberrant electrical activity in the brain. Over ten million people worldwide suffer from drug-resistant epilepsy. This severe condition requires novel treatment approaches. Both oxidative and nitrosative stress are thought to have a role in the etiology of epilepsy. Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that is used to treat type-2 diabetes mellitus. According to recent studies, Liraglutide also shows neuroprotective properties, improving memory retention and total hippocampus pyramidal neuronal population in mice. The purpose of this investigation was to determine the anti-seizure and anti-oxidative effects of liraglutide in a pentylenetetrazole (PTZ)-induced rat model of epilepsy. 48 rats were randomly assigned to two groups: those who had electroencephalography (EEG) recordings and those who underwent behavioral assessment. Rats received either intraperitoneal (IP) liraglutide at two different dosages (3-6 mg/kg) or a placebo, followed by pentylenetetrazole (IP). To determine if liraglutide has anti-seizure characteristics, we examined seizure activity in rats using EEG, the Racine convulsion scale (RCS), the time of first myoclonic jerk (FMJ), and MDA, SOD, TNF-α, IL-1β and GAD-67 levels. The mean EEG spike wave percentage score was reduced from 75.8% (placebo) to 59.4% (lower-dose) and 41.5% (higher-dose). FMJ had increased from a mean of 70.6 s (placebo) to 181.2 s (lower-dose) and 205.2 s (higher-dose). RCS was reduced from a mean of 5.5 (placebo) to 2.7 (lower-dose) and 2.4 (higher-dose). Liraglutide (3 and 6 mg/kg i.p.) successfully decreased the spike percentages and RCS associated with PTZ induced epilepsy, as well as considerably decreased MDA, TNF-α, IL-1β and elevated SOD, GAD-67 levels in rat brain. Liraglutide significantly decreased seizure activity at both dosages when compared to control, most likely due to its anti-oxidant and anti-inflammatory properties. The potential clinical role of liraglutide as an anti-seizure medication should be further explored.
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26
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Paredes GF, Viehboeck T, Markert S, Mausz MA, Sato Y, Liebeke M, König L, Bulgheresi S. Differential regulation of degradation and immune pathways underlies adaptation of the ectosymbiotic nematode Laxus oneistus to oxic-anoxic interfaces. Sci Rep 2022; 12:9725. [PMID: 35697683 PMCID: PMC9192688 DOI: 10.1038/s41598-022-13235-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 05/13/2022] [Indexed: 11/09/2022] Open
Abstract
Eukaryotes may experience oxygen deprivation under both physiological and pathological conditions. Because oxygen shortage leads to a reduction in cellular energy production, all eukaryotes studied so far conserve energy by suppressing their metabolism. However, the molecular physiology of animals that naturally and repeatedly experience anoxia is underexplored. One such animal is the marine nematode Laxus oneistus. It thrives, invariably coated by its sulfur-oxidizing symbiont Candidatus Thiosymbion oneisti, in anoxic sulfidic or hypoxic sand. Here, transcriptomics and proteomics showed that, whether in anoxia or not, L. oneistus mostly expressed genes involved in ubiquitination, energy generation, oxidative stress response, immune response, development, and translation. Importantly, ubiquitination genes were also highly expressed when the nematode was subjected to anoxic sulfidic conditions, together with genes involved in autophagy, detoxification and ribosome biogenesis. We hypothesize that these degradation pathways were induced to recycle damaged cellular components (mitochondria) and misfolded proteins into nutrients. Remarkably, when L. oneistus was subjected to anoxic sulfidic conditions, lectin and mucin genes were also upregulated, potentially to promote the attachment of its thiotrophic symbiont. Furthermore, the nematode appeared to survive oxygen deprivation by using an alternative electron carrier (rhodoquinone) and acceptor (fumarate), to rewire the electron transfer chain. On the other hand, under hypoxia, genes involved in costly processes (e.g., amino acid biosynthesis, development, feeding, mating) were upregulated, together with the worm's Toll-like innate immunity pathway and several immune effectors (e.g., bactericidal/permeability-increasing proteins, fungicides). In conclusion, we hypothesize that, in anoxic sulfidic sand, L. oneistus upregulates degradation processes, rewires the oxidative phosphorylation and reinforces its coat of bacterial sulfur-oxidizers. In upper sand layers, instead, it appears to produce broad-range antimicrobials and to exploit oxygen for biosynthesis and development.
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Affiliation(s)
- Gabriela F Paredes
- Department of Functional and Evolutionary Ecology, Environmental Cell Biology Group, University of Vienna, Vienna, Austria
| | - Tobias Viehboeck
- Department of Functional and Evolutionary Ecology, Environmental Cell Biology Group, University of Vienna, Vienna, Austria
- Vienna Doctoral School of Ecology and Evolution, Vienna, Austria
- Division of Microbial Ecology, Center for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria
| | - Stephanie Markert
- Department of Pharmaceutical Biotechnology, Institute of Pharmacy, University of Greifswald, Greifswald, Germany
| | | | - Yui Sato
- Max Planck Institute for Marine Microbiology, Bremen, Germany
| | - Manuel Liebeke
- Max Planck Institute for Marine Microbiology, Bremen, Germany
| | - Lena König
- Department of Functional and Evolutionary Ecology, Environmental Cell Biology Group, University of Vienna, Vienna, Austria
| | - Silvia Bulgheresi
- Department of Functional and Evolutionary Ecology, Environmental Cell Biology Group, University of Vienna, Vienna, Austria.
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27
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Canzian J, Gonçalves FLS, Müller TE, Franscescon F, Santos LW, Adedara IA, Rosemberg DB. Zebrafish as a potential non-traditional model organism in translational bipolar disorder research: Genetic and behavioral insights. Neurosci Biobehav Rev 2022; 136:104620. [PMID: 35300991 DOI: 10.1016/j.neubiorev.2022.104620] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 02/16/2022] [Accepted: 03/10/2022] [Indexed: 01/14/2023]
Abstract
Bipolar disorder (BD) is a severe and debilitating illness that affects 1-2% of the population worldwide. BD is characterized by recurrent and extreme mood swings, including mania/hypomania and depression. Animal experimental models have been used to elucidate the mechanisms underlying BD and different strategies have been proposed to assess BD-like symptoms. The zebrafish (Danio rerio) has been considered a suitable vertebrate system for modeling BD-like responses, due to the genetic tractability, molecular/physiological conservation, and well-characterized behavioral responses. In this review, we discuss how zebrafish-based models can be successfully used to understand molecular, biochemical, and behavioral alterations paralleling those found in BD. We also outline some advantages and limitations of this aquatic species to examine BD-like phenotypes in translational neurobehavioral research. Overall, we reinforce the use of zebrafish as a promising tool to investigate the neural basis associated with BD-like behaviors, which may foster the discovery of novel pharmacological therapies.
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Affiliation(s)
- Julia Canzian
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil; Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil
| | - Falco L S Gonçalves
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil
| | - Talise E Müller
- Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil
| | - Francini Franscescon
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil; Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil
| | - Laura W Santos
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil
| | - Isaac A Adedara
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil; Drug Metabolism and Toxicology Research Laboratories, Department of Biochemistry, College of Medicine, University of Ibadan, Ibadan, Nigeria.
| | - Denis B Rosemberg
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil; Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil; The International Zebrafish Neuroscience Research Consortium (ZNRC), 309 Palmer Court, Slidell, LA 70458, USA.
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28
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Prdm12 regulates inhibitory neuron differentiation in mouse embryonal carcinoma cells. Cytotechnology 2022; 74:329-339. [PMID: 35464160 PMCID: PMC8975904 DOI: 10.1007/s10616-022-00519-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 01/04/2022] [Indexed: 11/03/2022] Open
Abstract
The epigenetic regulatory system significant influences the fate determination of cells during developmental processes. Prdm12 is a transcriptional regulator that modulates gene expression epigenetically. The Prdm12 gene has been shown to be expressed in neural tissues, specifically during development, but its detailed function is not fully understood. This study investigated the function of the Prdm12 gene in P19 mouse embryonic tumor cells as a model for neural differentiation. A decrease in the expression of neuron-specific genes and the alterations of dendrites and axons morphology was confirmed in Prdm12-knockout P19 cells. In addition, almost no astrocytes were generated in Prdm12-knockout P19 cells. Comprehensive gene expression analysis revealed that there was a reduction in the expression of the inhibitory neuron-specific genes Gad1/2 and Glyt2, but not the excitatory neuron-specific gene VGLUT2, in Prdm12-knockout P19 cells. Furthermore, the expression of inhibitory neuron-related factors, Ptf1a, Dbx1, and Gsx1/2, decreased in Prdm12-knockout P19 cells. Gene expression analysis also revealed that the Ptf1a, Hic1, and Foxa1 genes were candidate targets of Prdm12 during neurogenesis. These results suggest that Prdm12 regulates the differentiation of inhibitory neurons and astrocytes by controlling the expression of these genes during the neural differentiation of P19 cells.
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29
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Shimizu-Okabe C, Kobayashi S, Kim J, Kosaka Y, Sunagawa M, Okabe A, Takayama C. Developmental Formation of the GABAergic and Glycinergic Networks in the Mouse Spinal Cord. Int J Mol Sci 2022; 23:ijms23020834. [PMID: 35055019 PMCID: PMC8776010 DOI: 10.3390/ijms23020834] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/07/2022] [Accepted: 01/11/2022] [Indexed: 12/15/2022] Open
Abstract
Gamma-aminobutyric acid (GABA) and glycine act as inhibitory neurotransmitters. Three types of inhibitory neurons and terminals, GABAergic, GABA/glycine coreleasing, and glycinergic, are orchestrated in the spinal cord neural circuits and play critical roles in regulating pain, locomotive movement, and respiratory rhythms. In this study, we first describe GABAergic and glycinergic transmission and inhibitory networks, consisting of three types of terminals in the mature mouse spinal cord. Second, we describe the developmental formation of GABAergic and glycinergic networks, with a specific focus on the differentiation of neurons, formation of synapses, maturation of removal systems, and changes in their action. GABAergic and glycinergic neurons are derived from the same domains of the ventricular zone. Initially, GABAergic neurons are differentiated, and their axons form synapses. Some of these neurons remain GABAergic in lamina I and II. Many GABAergic neurons convert to a coreleasing state. The coreleasing neurons and terminals remain in the dorsal horn, whereas many ultimately become glycinergic in the ventral horn. During the development of terminals and the transformation from radial glia to astrocytes, GABA and glycine receptor subunit compositions markedly change, removal systems mature, and GABAergic and glycinergic action shifts from excitatory to inhibitory.
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Affiliation(s)
- Chigusa Shimizu-Okabe
- Department of Molecular Anatomy, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara 903-0215, Japan; (C.S.-O.); (S.K.); (Y.K.); (M.S.)
| | - Shiori Kobayashi
- Department of Molecular Anatomy, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara 903-0215, Japan; (C.S.-O.); (S.K.); (Y.K.); (M.S.)
| | - Jeongtae Kim
- Department of Anatomy, Kosin University College of Medicine, Busan 49267, Korea;
| | - Yoshinori Kosaka
- Department of Molecular Anatomy, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara 903-0215, Japan; (C.S.-O.); (S.K.); (Y.K.); (M.S.)
| | - Masanobu Sunagawa
- Department of Molecular Anatomy, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara 903-0215, Japan; (C.S.-O.); (S.K.); (Y.K.); (M.S.)
| | - Akihito Okabe
- Department of Nutritional Science, Faculty of Health and Welfare, Seinan Jo Gakuin University, Fukuoka 803-0835, Japan;
| | - Chitoshi Takayama
- Department of Molecular Anatomy, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara 903-0215, Japan; (C.S.-O.); (S.K.); (Y.K.); (M.S.)
- Correspondence: ; Tel.: +81-98-895-1103 or +81-895-1405
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30
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Cherix A, Poitry-Yamate C, Lanz B, Zanoletti O, Grosse J, Sandi C, Gruetter R, Cardinaux JR. Deletion of Crtc1 leads to hippocampal neuroenergetic impairments associated with depressive-like behavior. Mol Psychiatry 2022; 27:4485-4501. [PMID: 36224260 PMCID: PMC9734042 DOI: 10.1038/s41380-022-01791-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 12/15/2022]
Abstract
Mood disorders (MD) are a major burden on society as their biology remains poorly understood, challenging both diagnosis and therapy. Among many observed biological dysfunctions, homeostatic dysregulation, such as metabolic syndrome (MeS), shows considerable comorbidity with MD. Recently, CREB-regulated transcription coactivator 1 (CRTC1), a regulator of brain metabolism, was proposed as a promising factor to understand this relationship. Searching for imaging biomarkers and associating them with pathophysiological mechanisms using preclinical models can provide significant insight into these complex psychiatric diseases and help the development of personalized healthcare. Here, we used neuroimaging technologies to show that deletion of Crtc1 in mice leads to an imaging fingerprint of hippocampal metabolic impairment related to depressive-like behavior. By identifying a deficiency in hippocampal glucose metabolism as the underlying molecular/physiological origin of the markers, we could assign an energy-boosting mood-stabilizing treatment, ebselen, which rescued behavior and neuroimaging markers. Finally, our results point toward the GABAergic system as a potential therapeutic target for behavioral dysfunctions related to metabolic disorders. This study provides new insights on Crtc1's and MeS's relationship to MD and establishes depression-related markers with clinical potential.
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Affiliation(s)
- Antoine Cherix
- Laboratory for Functional and Metabolic Imaging (LIFMET), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. .,Center for Psychiatric Neuroscience and Service of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Prilly-Lausanne, Switzerland.
| | - Carole Poitry-Yamate
- grid.5333.60000000121839049Animal Imaging and Technology (AIT), Center for Biomedical Imaging (CIBM), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Bernard Lanz
- grid.5333.60000000121839049Laboratory for Functional and Metabolic Imaging (LIFMET), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Olivia Zanoletti
- grid.5333.60000000121839049Laboratory of Behavioral Genetics, Brain and Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Jocelyn Grosse
- grid.5333.60000000121839049Laboratory of Behavioral Genetics, Brain and Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Carmen Sandi
- grid.5333.60000000121839049Laboratory of Behavioral Genetics, Brain and Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Rolf Gruetter
- grid.5333.60000000121839049Laboratory for Functional and Metabolic Imaging (LIFMET), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Jean-René Cardinaux
- Center for Psychiatric Neuroscience and Service of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Prilly-Lausanne, Switzerland.
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31
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Jiang W, Kakizaki T, Fujihara K, Miyata S, Zhang Y, Suto T, Kato D, Saito S, Shibasaki K, Ishizaki Y, Isoda K, Yokoo H, Obinata H, Hirano T, Miyasaka Y, Mashimo T, Yanagawa Y. Impact of GAD65 and/or GAD67 deficiency on perinatal development in rats. FASEB J 2022; 36:e22123. [PMID: 34972242 DOI: 10.1096/fj.202101389r] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 11/26/2021] [Accepted: 12/13/2021] [Indexed: 11/11/2022]
Abstract
GABA is a major neurotransmitter in the mammalian central nervous system. Glutamate decarboxylase (GAD) synthesizes GABA from glutamate, and two isoforms of GAD, GAD65, and GAD67, are separately encoded by the Gad2 and Gad1 genes, respectively. The phenotypes differ in severity between GAD single isoform-deficient mice and rats. For example, GAD67 deficiency causes cleft palate and/or omphalocele in mice but not in rats. In this study, to further investigate the functional roles of GAD65 and/or GAD67 and to determine the contribution of these isoforms to GABA synthesis during development, we generated various kinds of GAD isoform(s)-deficient rats and characterized their phenotypes. The age of death was different among Gad mutant rat genotypes. In particular, all Gad1-/- ; Gad2-/- rats died at postnatal day 0 and showed little alveolar space in their lungs, suggesting that the cause of their death was respiratory failure. All Gad1-/- ; Gad2-/- rats and 18% of Gad1-/- ; Gad2+/- rats showed cleft palate. In contrast, none of the Gad mutant rats including Gad1-/- ; Gad2-/- rats, showed omphalocele. These results suggest that both rat GAD65 and GAD67 are involved in palate formation, while neither isoform is critical for abdominal wall formation. The GABA content in Gad1-/- ; Gad2-/- rat forebrains and retinas at embryonic day 20 was extremely low, indicating that almost all GABA was synthesized from glutamate by GADs in the perinatal period. The present study shows that Gad mutant rats are a good model for further defining the role of GABA during development.
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Affiliation(s)
- Weiru Jiang
- Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Toshikazu Kakizaki
- Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Kazuyuki Fujihara
- Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Shigeo Miyata
- Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Yue Zhang
- Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan.,Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology, Dalian Medical University, Dalian, China
| | - Takashi Suto
- Department of Anesthesiology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Daiki Kato
- Department of Anesthesiology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Shigeru Saito
- Department of Anesthesiology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Koji Shibasaki
- Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Yasuki Ishizaki
- Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Koji Isoda
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Hideaki Yokoo
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Hideru Obinata
- Laboratory for Analytical Instruments, Education and Research Support Center, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Touko Hirano
- Laboratory for Analytical Instruments, Education and Research Support Center, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Yoshiki Miyasaka
- Institute of Experimental Animal Sciences, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Tomoji Mashimo
- Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yuchio Yanagawa
- Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan
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Kajita Y, Mushiake H. Heterogeneous GAD65 Expression in Subtypes of GABAergic Neurons Across Layers of the Cerebral Cortex and Hippocampus. Front Behav Neurosci 2021; 15:750869. [PMID: 34803625 PMCID: PMC8595203 DOI: 10.3389/fnbeh.2021.750869] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 09/16/2021] [Indexed: 11/13/2022] Open
Abstract
Gamma-aminobutyric acid (GABA), a major inhibitory transmitter in the central nervous system, is synthesized via either of two enzyme isoforms, GAD65 or GAD67. GAD65 is synthesized in the soma but functions at synaptic terminals in an activity-dependent manner, playing a distinct role in excitatory-inhibitory balance. However, the extent to which each GABAergic subtype expresses GAD65 in the resting state remains unclear. In this study, we compared GAD65 expression among six GABAergic subtypes: NPY+, nNOS+, PV+, SOM+, CR+, and CCK+. According to the results, the GABAergic subtypes were classified into two groups per region based on GAD65 expression levels: high-expression (NPY+ and nNOS+) and low-expression groups (PV+, SOM+, CR+, and CCK+) in the cerebral cortex and high-expression (NPY+, nNOS+, and CCK+) and low-expression groups (PV+, SOM+, and CR+) in the hippocampus. Moreover, these expression patterns revealed a distinct laminar distribution in the cerebral cortex and hippocampus. To investigate the extent of GAD65 transport from the soma to synaptic terminals, we examined GAD65 expression in colchicine-treated rats in which GAD65 was synthesized in the soma but not transported to terminals. We found a significant positive correlation in GAD65 expression across subtypes between colchicine-treated and control rats. In summary, each GABAergic subtype exhibits a distinct GAD65 expression pattern across layers of the cerebral cortex and hippocampus. In addition, the level of GAD65 expression in the soma can be used as a proxy for the amount of GAD65 in the cytoplasm. These findings suggest that exploration of the distinct profiles of GAD65 expression among GABAergic subtypes could clarify the roles that GABAergic subtypes play in maintaining the excitatory-inhibitory balance.
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Affiliation(s)
- Yuki Kajita
- Department of Physiology, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Hajime Mushiake
- Department of Physiology, Graduate School of Medicine, Tohoku University, Sendai, Japan
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Motaghi S, Moghaddam Dizaj Herik H, Sepehri G, Abbasnejad M, Esmaeli-Mahani S. The anxiolytic effect of salicylic acid is mediated via the GABAergic system in the fear potentiated plus maze behavior in rats. Mol Biol Rep 2021; 49:1133-1139. [PMID: 34797490 DOI: 10.1007/s11033-021-06939-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 11/05/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Salicylic acid (SA) is a natural phenolic compound in plants with many beneficial effects for humans. The anxiolytic effect of this compound has been reported in animal models, but its mechanism of action remains unclear. In this study, by using the fear potentiated plus maze test, we evaluated the effect of salicylic acid on the gene expression of the main form of GABA (gamma aminobutyric acid) synthesizing enzyme i.e., the enzyme glutamic acid decarboxylase 67 (GAD67) which is called GAD1, in the ventral subiculum of the hippocampus, one of the main brain structures, in anxiety circuits. Also, the hypnotic effect of Salicylic acid was evaluated. METHODS Animals were divided into the solvent, (SA) and diazepam treated groups (n = 6). For evaluating the anxiolytic effect of Salicylic acid, animals were subjected to 2 h of isolation, before placing them in the elevated plus maze (EPM). Afterward, the ventral part of the hippocampus was removed for evaluating the change in GAD1 gene expression by the reverse transcription-quantitative polymerase chain reaction (RTqPCR) technique. The hypnotic effect of Salicylic acid was evaluated in the ketamine induced sleeping test. RESULTS Salicylic acid at 10 and 30 (mg/kg) increased time spent and entries to the open arms in the (EPM) (p < 0.05). (RTqPCR) revealed that 30 mg/kg of Salicylic acid increased GAD1 gene expression (p < 0.001). Salicylic acid (30 and 300 mg/kg) also increased the duration of sleep, in ketamine induced sleeping test (p < 0.05). CONCLUSION Our results showed that Salicylic acid has anxiolytic and hypnotic effects and it exerts its anxiolytic effect partly, via up the regulation of GAD1 in the ventral part of the hippocampus.
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Affiliation(s)
- Sahel Motaghi
- Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran.
| | - Hadi Moghaddam Dizaj Herik
- Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Gholamreza Sepehri
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mehdi Abbasnejad
- Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Saeed Esmaeli-Mahani
- Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran
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Della Vecchia A, Arone A, Piccinni A, Mucci F, Marazziti D. GABA System in Depression: Impact on Pathophysiology and Psychopharmacology. Curr Med Chem 2021; 29:5710-5730. [PMID: 34781862 DOI: 10.2174/0929867328666211115124149] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 09/21/2021] [Accepted: 09/30/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The pathophysiology of major depressive disorder (MDD), one of the major causes of worldwide disability, is still largely unclear, despite the increasing data reporting evidence of multiple alterations of different systems. Recently, there was a renewed interest in the signalling of gamma aminobutyric acid (GABA) - the main inhibitory neurotransmitter. OBJECTIVE The aim of this study was to review and comment on the available literature about the involvement of GABA in MDD, as well as on novel GABAergic compounds possibly useful as antidepressants. METHODS We carried out a narrative review through Pubmed, Google Scholar and Scopus, by using specific keywords. RESULTS The results, derived from various research tools, strongly support the presence of a deficiency of the GABA system in MDD, which appears to be restored by common antidepressant treatments. More recent publications would indicate the complex interactions between GABA and all the other processes involved in MDD, such as monoamine neurotransmission, hypothalamus-pituitary adrenal axis functioning, neurotrophism, and immune response. Taken together, all these findings seem to further support the complexity of the pathophysiology of MDD, possibly reflecting the heterogeneity of the clinical pictures. CONCLUSION Although further data are necessary to support the specificity of GABA deficiency in MDD, the available findings would suggest that novel GABAergic compounds might constitute innovative therapeutic strategies in MDD.
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Affiliation(s)
- Alessandra Della Vecchia
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa. Italy
| | - Alessandro Arone
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa. Italy
| | - Armando Piccinni
- Saint Camillus International University of Health and Medical Sciences, Rome. Italy
| | - Federico Mucci
- Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena. Italy
| | - Donatella Marazziti
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa. Italy
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35
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Coupling of GABA Metabolism to Mitochondrial Glucose Phosphorylation. Neurochem Res 2021; 47:470-480. [PMID: 34623563 DOI: 10.1007/s11064-021-03463-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 09/15/2021] [Accepted: 10/04/2021] [Indexed: 10/20/2022]
Abstract
Glucose and oxygen (O2) are vital to the brain. Glucose metabolism and mitochondria play a pivotal role in this process, culminating in the increase of reactive O2 species. Hexokinase (HK) is a key enzyme on glucose metabolism and is coupled to the brain mitochondrial redox modulation by recycling ADP for oxidative phosphorylation (OXPHOS). GABA shunt is an alternative pathway to GABA metabolism that increases succinate levels, a Krebs cycle intermediate. Although glucose and GABA metabolisms are intrinsically connected, their interplay coordinating mitochondrial function is poorly understood. Here, we hypothesize that the HK and the GABA shunt interact to control mitochondrial metabolism differently in the cortex and the hypothalamus. The GABA shunt stimulated mitochondrial O2 consumption and H2O2 production higher in hypothalamic synaptosomes (HSy) than cortical synaptosomes (CSy). The GABA shunt increased the HK coupled to OXPHOS activity in both population of synaptosomes, but the rate of activation was higher in HSy than CSy. Significantly, malonate and vigabatrin blocked the effects of the GABA shunt in the HK activity coupled to OXPHOS. It indicates that the glucose phosphorylation is linked to GABA and Krebs cycle reactions. Together, these data shed light on the HK and SDH role on the metabolism of each region fed by GABA turnover, which depends on the neurons' metabolic route.
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36
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d'Adesky N, Diaz F, Zhao W, Bramlett HM, Perez-Pinzon MA, Dave KR, Raval AP. Nicotine Exposure Along with Oral Contraceptive Treatment in Female Rats Exacerbates Post-cerebral Ischemic Hypoperfusion Potentially via Altered Histamine Metabolism. Transl Stroke Res 2021; 12:817-828. [PMID: 33130995 PMCID: PMC12121693 DOI: 10.1007/s12975-020-00854-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 09/19/2020] [Accepted: 09/23/2020] [Indexed: 10/23/2022]
Abstract
Smoking-derived nicotine (N) and oral contraceptives (OCs) synergistically exacerbate ischemic brain damage in the female, and the underlying mechanisms remain elusive. Our published study showed that N toxicity is exacerbated by OC via altered mitochondrial electron transport chain function. Because mitochondria play an important role in cellular metabolism, we investigated the global metabolomic profile of brains of adolescent and adult female Sprague-Dawley rats exposed to N with or without OC (N+/-OC). Rats were randomly exposed to saline or N+/-OC for 16-21 days followed by random allocation into two cohorts. The first cohort was used to characterize the cortical metabolome. Pathway enrichment analysis showed a significant increase in several histamine metabolites including 1-methylhistamine, 1-methyl-4-imidazoleacetate, and 1-ribosyl-imidazleacetate, along with carnosine and homocarnosine in adolescent and adult animals treated with N and N+OC in relation to respective saline controls, which may be reflective of altered histamine metabolism with nicotine treatment. We also observed reduced levels of the neurotransmitters N-acetyl-aspartyl-glutamate (NAAG), gamma-aminobutyrate (GABA), and N-methyl-GABA in N+OC treatment in adolescent animals. The second cohort underwent bilateral carotid artery occlusion and hypotension followed by cerebral blood flow (CBF) assessment a day later. Autoradiographic images of the brain 24 h after ischemic episodes showed severe reduction in cortical and hippocampal local CBF in N+/-OC-exposed rats compared with saline treated. Because GABA and histamine are critical for CBF maintenance, altered metabolism of these neurotransmitters may be responsible for observed severe post-ischemic hypoperfusion, which in turn exacerbates ischemic brain damage.
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Affiliation(s)
- Nathan d'Adesky
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, 1420 NW 9th Avenue, Neurology Research Building, Room # 203H, Miami, FL, 33136, USA
| | - Francisca Diaz
- Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Weizhao Zhao
- Biomedical Engineering, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Helen M Bramlett
- Department of Neurological Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
- Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL, USA
| | - Miguel A Perez-Pinzon
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, 1420 NW 9th Avenue, Neurology Research Building, Room # 203H, Miami, FL, 33136, USA
| | - Kunjan R Dave
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, 1420 NW 9th Avenue, Neurology Research Building, Room # 203H, Miami, FL, 33136, USA
| | - Ami P Raval
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, 1420 NW 9th Avenue, Neurology Research Building, Room # 203H, Miami, FL, 33136, USA.
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Cognitive control affects motor learning through local variations in GABA within the primary motor cortex. Sci Rep 2021; 11:18566. [PMID: 34535725 PMCID: PMC8448760 DOI: 10.1038/s41598-021-97974-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 08/27/2021] [Indexed: 02/08/2023] Open
Abstract
The primary motor cortex (M1) is crucial for motor learning; however, its interaction with other brain areas during motor learning remains unclear. We hypothesized that the fronto-parietal execution network (FPN) provides learning-related information critical for the flexible cognitive control that is required for practice. We assessed network-level changes during sequential finger tapping learning under speed pressure by combining magnetic resonance spectroscopy and task and resting-state functional magnetic resonance imaging. There was a motor learning-related increase in preparatory activity in the fronto-parietal regions, including the right M1, overlapping the FPN and sensorimotor network (SMN). Learning-related increases in M1-seeded functional connectivity with the FPN, but not the SMN, were associated with decreased GABA/glutamate ratio in the M1, which were more prominent in the parietal than the frontal region. A decrease in the GABA/glutamate ratio in the right M1 was positively correlated with improvements in task performance (p = 0.042). Our findings indicate that motor learning driven by cognitive control is associated with local variations in the GABA/glutamate ratio in the M1 that reflects remote connectivity with the FPN, representing network-level motor sequence learning formations.
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Elmaleh DR, Downey MA, Kundakovic L, Wilkinson JE, Neeman Z, Segal E. New Approaches to Profile the Microbiome for Treatment of Neurodegenerative Disease. J Alzheimers Dis 2021; 82:1373-1401. [PMID: 34219718 DOI: 10.3233/jad-210198] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Progressive neurodegenerative diseases represent some of the largest growing treatment challenges for public health in modern society. These diseases mainly progress due to aging and are driven by microglial surveillance and activation in response to changes occurring in the aging brain. The lack of efficacious treatment options for Alzheimer's disease (AD), as the focus of this review, and other neurodegenerative disorders has encouraged new approaches to address neuroinflammation for potential treatments. Here we will focus on the increasing evidence that dysbiosis of the gut microbiome is characterized by inflammation that may carry over to the central nervous system and into the brain. Neuroinflammation is the common thread associated with neurodegenerative diseases, but it is yet unknown at what point and how innate immune function turns pathogenic for an individual. This review will address extensive efforts to identify constituents of the gut microbiome and their neuroactive metabolites as a peripheral path to treatment. This approach is still in its infancy in substantive clinical trials and requires thorough human studies to elucidate the metabolic microbiome profile to design appropriate treatment strategies for early stages of neurodegenerative disease. We view that in order to address neurodegenerative mechanisms of the gut, microbiome and metabolite profiles must be determined to pre-screen AD subjects prior to the design of specific, chronic titrations of gut microbiota with low-dose antibiotics. This represents an exciting treatment strategy designed to balance inflammatory microglial involvement in disease progression with an individual's manifestation of AD as influenced by a coercive inflammatory gut.
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Affiliation(s)
- David R Elmaleh
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.,AZTherapies, Inc., Boston, MA, USA
| | | | | | - Jeremy E Wilkinson
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Ziv Neeman
- Department of Radiology, Emek Medical Center, Afula, Israel.,Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Eran Segal
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.,Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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United States Pharmacopeia (USP) Safety Review of Gamma-Aminobutyric Acid (GABA). Nutrients 2021; 13:nu13082742. [PMID: 34444905 PMCID: PMC8399837 DOI: 10.3390/nu13082742] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 08/04/2021] [Accepted: 08/05/2021] [Indexed: 11/24/2022] Open
Abstract
Gamma-amino butyric acid (GABA) is marketed in the U.S. as a dietary supplement. USP conducted a comprehensive safety evaluation of GABA by assessing clinical studies, adverse event information, and toxicology data. Clinical studies investigated the effect of pure GABA as a dietary supplement or as a natural constituent of fermented milk or soy matrices. Data showed no serious adverse events associated with GABA at intakes up to 18 g/d for 4 days and in longer studies at intakes of 120 mg/d for 12 weeks. Some studies showed that GABA was associated with a transient and moderate drop in blood pressure (<10% change). No studies were available on effects of GABA during pregnancy and lactation, and no case reports or spontaneous adverse events associated with GABA were found. Chronic administration of GABA to rats and dogs at doses up to 1 g/kg/day showed no signs of toxicity. Because some studies showed that GABA was associated with decreases in blood pressure, it is conceivable that concurrent use of GABA with anti-hypertensive medications could increase risk of hypotension. Caution is advised for pregnant and lactating women since GABA can affect neurotransmitters and the endocrine system, i.e., increases in growth hormone and prolactin levels.
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40
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Kang D, Hesam-Shariati N, McAuley JH, Alam M, Trost Z, Rae CD, Gustin SM. Disruption to normal excitatory and inhibitory function within the medial prefrontal cortex in people with chronic pain. Eur J Pain 2021; 25:2242-2256. [PMID: 34242465 DOI: 10.1002/ejp.1838] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Growing evidence indicates a link between changes in the medial prefrontal cortex and the pathophysiology of chronic pain. In particular, chronic pain is associated with altered medial prefrontal anatomy and biochemistry. Due to the comorbid affective disorders seen across all pain conditions, the medial prefrontal cortex is a region of significance as it is involved in emotional processing. We have recently reported that a decrease in medial prefrontal N-acetylaspartate and glutamate is associated with increased emotional dysregulation, indicating there are neurotransmitter imbalances in chronic pain. Therefore, we compared medial prefrontal neurochemistry in 24 people with chronic pain conditions to 24 age and sex-matched healthy controls with no history of chronic pain. METHOD GABA-edited MEGA-PRESS was used to measure GABA+ levels, and short TE PRESS was used to measure glutamate levels in the medial prefrontal cortex. Psychometric measures regarding pain intensity a week before scanning, during the scan and the total duration of chronic pain, were also recorded and compared to measured GABA+ and glutamate levels. RESULTS This study reveals that the presence of chronic pain is associated with significant decreases in medial prefrontal GABA+ and glutamate. These findings support the hypothesis that chronic pain is associated with altered medial prefrontal biochemistry. CONCLUSION The dysregulation of glutamatergic and GABAergic neurotransmitter systems supports a model of disinhibition of chronic pain, which may play a key role in both the experience of persistent pain and its associated affective disturbances. SIGNIFICANCE This study reveals a significant reduction in γ-aminobutyric acid (GABA+ ) and glutamate within the medial prefrontal cortex in chronic pain sufferers. While the current findings should be considered with reference to a small sample size, the disruption to normal excitatory and inhibitory medial prefrontal cortex function may be key in the development and maintenance of chronic pain and comorbid mental health disorders.
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Affiliation(s)
- David Kang
- Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, NSW, Australia
| | - Negin Hesam-Shariati
- Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, NSW, Australia.,School of Psychology, University of New South, Sydney, NSW, Australia
| | - James H McAuley
- Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, NSW, Australia.,School of Health Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Monzurul Alam
- Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, NSW, Australia.,School of Psychology, University of New South, Sydney, NSW, Australia
| | - Zina Trost
- Department of Physical Medicine and Rehabilitation, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Sylvia M Gustin
- Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, NSW, Australia.,School of Psychology, University of New South, Sydney, NSW, Australia
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41
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He Z, Liu Z, Gong L. Biomarker identification and pathway analysis of rheumatoid arthritis based on metabolomics in combination with ingenuity pathway analysis. Proteomics 2021; 21:e2100037. [PMID: 33969925 DOI: 10.1002/pmic.202100037] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/30/2021] [Accepted: 04/30/2021] [Indexed: 12/19/2022]
Abstract
Rheumatoid arthritis (RA) is a common autoimmune and inflammatory disease worldwide, but understanding its pathogenesis is still limited. In this study, plasma untargeted metabolomics of a discovery cohort and targeted analysis of a verification cohort were performed by gas chromatograph mass spectrometry (GC/MS). Univariate and multivariate statistical analysis were utilized to reveal differential metabolites, followed by the construction of biomarker panel through random forest (RF) algorithm. The pathways involved in RA were enriched by differential metabolites using Ingenuity Pathway Analysis (IPA) suite. Untargeted metabolomics revealed eighteen significantly altered metabolites in RA. Among these metabolites, a three-metabolite marker panel consisting of L-cysteine, citric acid and L-glutamine was constructed, using random forest algorithm that could predict RA with high accuracy, sensitivity and specificity based on a multivariate exploratory receiver operator characteristic (ROC) curve analysis. The panel was further validated by support vector machine (SVM) and partial least squares discriminant analysis (PLS-DA) algorithms, and also verified with targeted metabolomics using a verification cohort. Additionally, the dysregulated taurine biosynthesis pathway in RA was revealed by an integrated analysis of metabolomics and transcriptomics. Our findings in this study not only provided a mechanism underlying RA pathogenesis, but also offered alternative therapeutic targets for RA.
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Affiliation(s)
- Zhuoru He
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China
| | - Zhongqiu Liu
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China
| | - Lingzhi Gong
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China
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Basu SK, Pradhan S, du Plessis AJ, Ben-Ari Y, Limperopoulos C. GABA and glutamate in the preterm neonatal brain: In-vivo measurement by magnetic resonance spectroscopy. Neuroimage 2021; 238:118215. [PMID: 34058332 PMCID: PMC8404144 DOI: 10.1016/j.neuroimage.2021.118215] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/30/2021] [Accepted: 05/25/2021] [Indexed: 12/11/2022] Open
Abstract
Cognitive and behavioral disabilities in preterm infants, even without obvious brain injury on conventional neuroimaging, underscores a critical need to identify the subtle underlying microstructural and biochemical derangements. The gamma-aminobutyric acid (GABA) and glutamatergic neurotransmitter systems undergo rapid maturation during the crucial late gestation and early postnatal life, and are at-risk of disruption after preterm birth. Animal and human autopsy studies provide the bulk of current understanding since non-invasive specialized proton magnetic resonance spectroscopy (1H-MRS) to measure GABA and glutamate are not routinely available for this vulnerable population due to logistical and technical challenges. We review the specialized 1H-MRS techniques including MEscher-GArwood Point Resolved Spectroscopy (MEGA-PRESS), special challenges and considerations needed for interpretation of acquired data from the developing brain of preterm infants. We summarize the limited in-vivo preterm data, highlight the gaps in knowledge, and discuss future directions for optimal integration of available in-vivo approaches to understand the influence of GABA and glutamate on neurodevelopmental outcomes after preterm birth.
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Affiliation(s)
- Sudeepta K Basu
- Neonatology, Children's National Hospital, Washington, D.C., United States; Center for the Developing Brain, Children's National Hospital, Washington, D.C., United States; Division of Neurology, Children's National Hospital, Washington, D.C., United States; The George Washington University School of Medicine, Washington, D.C., United States
| | - Subechhya Pradhan
- Center for the Developing Brain, Children's National Hospital, Washington, D.C., United States; Division of Neurology, Children's National Hospital, Washington, D.C., United States; The George Washington University School of Medicine, Washington, D.C., United States
| | - Adre J du Plessis
- Fetal Medicine institute, Children's National Hospital, Washington, D.C., United States; Division of Neurology, Children's National Hospital, Washington, D.C., United States; The George Washington University School of Medicine, Washington, D.C., United States
| | - Yehezkel Ben-Ari
- Division of Neurology, Children's National Hospital, Washington, D.C., United States; Neurochlore, Marseille, France
| | - Catherine Limperopoulos
- Center for the Developing Brain, Children's National Hospital, Washington, D.C., United States; Division of Diagnostic Imaging and Radiology, Children's National Hospital, Washington, D.C., United States; Division of Neurology, Children's National Hospital, Washington, D.C., United States; The George Washington University School of Medicine, Washington, D.C., United States.
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Kida E, Walus M, Albertini G, Golabek AA. Long-term voluntary running modifies the levels of proteins of the excitatory/inhibitory system and reduces reactive astrogliosis in the brain of Ts65Dn mouse model for Down syndrome. Brain Res 2021; 1766:147535. [PMID: 34043998 DOI: 10.1016/j.brainres.2021.147535] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 05/20/2021] [Accepted: 05/22/2021] [Indexed: 09/30/2022]
Abstract
We showed previously that voluntary long-term running improved cognition and motor skills, but in an age-dependent manner, in the Ts65Dn mouse model for Down syndrome (DS). Presently, we investigated the effect of running on the levels of some key proteins of the excitatory/inhibitory system, which is impaired in the trisomic brain, and on astroglia, a vital component of this system. Ts65Dn mice had free access to a running wheel for 9-13 months either from weaning or from the age of 7 months. Sedentary Ts65Dn mice served as controls. We found that running modified the levels of four of the seven proteins we tested that are associated with the glutamatergic/GABA-ergic system. Thus, Ts65Dn runners demonstrated increased levels of glutamine synthetase and metabotropic glutamate receptor 1 and decreased levels of glutamate transporter 1 and glutamic acid decarboxylase 65 (GAD65) versus sedentary mice, but of metabotropic glutamate receptor 1 and GAD65 only in the post-weaning cohort. GAD67, ionotropic N-methyl-D-aspartate type receptor subunit 1, and GABAAα5 receptors' levels were similar in runners and sedentary animals. The number of glial fibrillary acidic protein (GFAP)-positive astrocytes and the levels of GFAP were significantly reduced in runners relative to sedentary mice. Our study provides new insight into the mechanisms underlying the beneficial effect of voluntary, sustained running on function of the trisomic brain by identifying the involvement of proteins associated with glutamatergic and GABAergic systems and reduction in reactive astrogliosis.
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Affiliation(s)
- Elizabeth Kida
- Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA
| | - Marius Walus
- Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA
| | - Giorgio Albertini
- Child Development Department, IRCCS San Raffaele Pisana, Rome and San Raffaele Cassino, Italy
| | - Adam A Golabek
- Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
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Integrative opioid-GABAergic neuronal mechanisms regulating dopamine efflux in the nucleus accumbens of freely moving animals. Pharmacol Rep 2021; 73:971-983. [PMID: 33743175 DOI: 10.1007/s43440-021-00249-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/26/2021] [Accepted: 03/11/2021] [Indexed: 01/14/2023]
Abstract
The nucleus accumbens (NAc) is a terminal region of mesocorticolimbic dopamine (DA) neuronal projections from the ventral tegmental area. Accumbal DA release is integrated by afferents from other brain regions and by interneurons, which involve a diversity of neurotransmitters and neuropeptides. These integrative processes, implicated in the pathobiology of neuropsychiatric disorders, are mediated via receptor subtypes whose relative roles in the regulation of accumbal DA release are poorly understood. Such complex interactions are exemplified by how selective activation of opioid receptor subtypes enhances accumbal DA efflux in a manner that is modulated by changes in neural activity through GABA receptor subtypes. This review delineates the roles of GABAA and GABAB receptors in GABAergic neural mechanisms in NAc that participate in delta- and mu-opioid receptor-mediated increases in accumbal DA efflux in freely moving rats, focusing on studies using in vivo brain microdialysis. First, we consider how endogenous GABA exerts inhibition of accumbal DA efflux through GABA receptor subtypes. We also consider possible intra-neuronal source of the endogenous GABA that inhibits accumbal DA efflux. As NAc contains GABAergic neurons that express delta- or mu-opioid receptors, inhibition of accumbal GABAergic neurons is a candidate for mediating delta- or mu-opioid receptor-mediated increases in accumbal DA efflux. Therefore, we provide a detailed analysis of the effects of GABA receptor subtype ligands on delta- and mu-opioid receptor-mediated accumbal DA efflux. Finally, we present an integrative model to explain the mechanisms of interaction among delta- and mu-opioid receptors, GABAergic neurons and DAergic neurons in NAc.
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Visual Attention Modulates Glutamate-Glutamine Levels in Vestibular Cortex: Evidence from Magnetic Resonance Spectroscopy. J Neurosci 2021; 41:1970-1981. [PMID: 33452222 DOI: 10.1523/jneurosci.2018-20.2020] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 11/12/2020] [Accepted: 12/22/2020] [Indexed: 11/21/2022] Open
Abstract
Attending to a stimulus enhances the neuronal responses to it, while responses to nonattended stimuli are not enhanced and may even be suppressed. Although the neural mechanisms of response enhancement for attended stimuli have been intensely studied, the neural mechanisms underlying attentional suppression remain largely unknown. It is uncertain whether attention acts to suppress the processing in sensory cortical areas that would otherwise process the nonattended stimulus or the subcortical input to these cortical areas. Moreover, the neurochemical mechanisms inducing a reduction or suppression of neuronal responses to nonattended stimuli are as yet unknown. Here, we investigated how attention directed toward visual processing cross-modally acts to suppress vestibular responses in the human brain. By using functional magnetic resonance spectroscopy in a group of female and male subjects, we find that attention to visual motion downregulates in a load-dependent manner the concentration of excitatory neurotransmitter (glutamate and its precursor glutamine, referred to together as Glx) within the parietoinsular vestibular cortex (PIVC), a core cortical area of the vestibular system, while leaving the concentration of inhibitory neurotransmitter (GABA) in PIVC unchanged. This makes PIVC less responsive to excitatory thalamic vestibular input, as corroborated by functional magnetic resonance imaging. Together, our results suggest that attention acts to suppress the processing of nonattended sensory cues cortically by neurochemically rendering the core cortical area of the nonattended sensory modality less responsive to excitatory thalamic input.SIGNIFICANCE STATEMENT Here, we address a fundamental problem that has eluded attention research for decades, namely, how the brain ignores irrelevant stimuli. To date, three classes of solutions to this problem have been proposed: (1) enhancement of GABAergic interneuron activity in cortex, (2) downregulation of glutamatergic cell activity in cortex; and (3) downregulation of neural activity in thalamic projection areas, which would then provide the cortex with less input. Here, we use magnetic resonance spectroscopy in humans and find support for the second hypothesis, implying that attention to one sensory modality involves the suppression of irrelevant stimuli of another sensory modality by downregulating glutamate in the cortex.
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Sears SM, Hewett SJ. Influence of glutamate and GABA transport on brain excitatory/inhibitory balance. Exp Biol Med (Maywood) 2021; 246:1069-1083. [PMID: 33554649 DOI: 10.1177/1535370221989263] [Citation(s) in RCA: 120] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
An optimally functional brain requires both excitatory and inhibitory inputs that are regulated and balanced. A perturbation in the excitatory/inhibitory balance-as is the case in some neurological disorders/diseases (e.g. traumatic brain injury Alzheimer's disease, stroke, epilepsy and substance abuse) and disorders of development (e.g. schizophrenia, Rhett syndrome and autism spectrum disorder)-leads to dysfunctional signaling, which can result in impaired cognitive and motor function, if not frank neuronal injury. At the cellular level, transmission of glutamate and GABA, the principle excitatory and inhibitory neurotransmitters in the central nervous system control excitatory/inhibitory balance. Herein, we review the synthesis, release, and signaling of GABA and glutamate followed by a focused discussion on the importance of their transport systems to the maintenance of excitatory/inhibitory balance.
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Affiliation(s)
- Sheila Ms Sears
- Department of Biology, Program in Neuroscience, 2029Syracuse University, Syracuse, NY 13244, USA
| | - Sandra J Hewett
- Department of Biology, Program in Neuroscience, 2029Syracuse University, Syracuse, NY 13244, USA
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Cherix A, Donati G, Lizarbe B, Lanz B, Poitry-Yamate C, Lei H, Gruetter R. Excitatory/inhibitory neuronal metabolic balance in mouse hippocampus upon infusion of [U- 13C 6]glucose. J Cereb Blood Flow Metab 2021; 41:282-297. [PMID: 32151224 PMCID: PMC8370000 DOI: 10.1177/0271678x20910535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Hippocampus plays a critical role in linking brain energetics and behavior typically associated to stress exposure. In this study, we aimed to simultaneously assess excitatory and inhibitory neuronal metabolism in mouse hippocampus in vivo by applying 18FDG-PET and indirect 13C magnetic resonance spectroscopy (1H-[13C]-MRS) at 14.1 T upon infusion of uniformly 13C-labeled glucose ([U-13C6]Glc). Improving the spectral fitting by taking into account variable decoupling efficiencies of [U-13C6]Glc and refining the compartmentalized model by including two γ-aminobutyric acid (GABA) pools permit us to evaluate the relative contributions of glutamatergic and GABAergic metabolism to total hippocampal neuroenergetics. We report that GABAergic activity accounts for ∼13% of total neurotransmission (VNT) and ∼27% of total neuronal TCA cycle (VTCA) in mouse hippocampus suggesting a higher VTCA/VNT ratio for inhibitory neurons compared to excitatory neurons. Finally, our results provide new strategies and tools for bringing forward the developments and applications of 13C-MRS in specific brain regions of small animals.
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Affiliation(s)
- Antoine Cherix
- Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Guillaume Donati
- Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Blanca Lizarbe
- Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Instituto de Investigaciones Biomedicas "Alberto Sols", CSIC-UAM, Madrid, Spain
| | - Bernard Lanz
- Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Sir Peter Mansfield Imaging Centre (SPMIC), School of Medicine, University of Nottingham, Nottingham, UK
| | - Carole Poitry-Yamate
- Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Hongxia Lei
- Center for Biomedical Imaging (CIBM-AIT), Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Rolf Gruetter
- Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Wang S, Deng Z, Wang J, Zhang W, Liu F, Xu J, Ma Y. Decreased GABAergic signaling, fewer parvalbumin-, somatostatin- and calretinin-positive neurons in brain of a rat model of simulated transport stress. Res Vet Sci 2020; 134:86-95. [PMID: 33360121 DOI: 10.1016/j.rvsc.2020.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 11/12/2020] [Accepted: 12/12/2020] [Indexed: 10/22/2022]
Abstract
Transport stress (TS) in animals lead to change in blood composition, brain structure, and the endocrine system as well as behavior. γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system (CNS), influences many physiological functions and plays a significant role in coping with stress. This study aimed to explore the effect of stress on behavior, HPA axis, GABA transmitters and the distribution of GABAergic interneurons in the prefrontal cortex (PFC) and striatum of the brain by a rat model of simulated transport stress (STS). Thirty-six male Sprague Dawley rats were randomly divided into a control group (n = 12, no stress), a TS1d group (n = 12, 2 h stress for 1 d) and a TS7d group (n = 12, 2 h stress each day for 7 d). After STS, the rats were subjected to open-field testing (OFT) followed by serologic analysis, colorimetry, Western blot and immunohistochemistry. The total score of the OFT showed the similar profile with serum concentrations of corticosterone (CORT) and norepinephrine (NE), which in the TS7d group were all higher than the TS1d group but lower than the control group. STS also reduced GABA, glutamate decarboxylase 67 (GAD67) and GABA transporter 1 (GAT1) expression in the TS1d and these markers were increased in the TS7d, suggesting that GABA was related to hypothalamic-pituitary-adrenal (HPA) axis activation under stress. The number of parvalbumin (PV)-, somatostatin (SOM)-, and calretinin (CR)- positive cells were decreased with stress increase. Our findings revealed that STS affected the behavior of rats, synthesis and release of GABA by altering the HPA axis.
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Affiliation(s)
- Shujing Wang
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Ziteng Deng
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Jia Wang
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Wenjun Zhang
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Fenghua Liu
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing 102206, China
| | - Jianqin Xu
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Yunfei Ma
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
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Aydin H, Engin A, Keleş S, Ertemur Z, Hekim N. Glutamine depletion in patients with Crimean-Congo hemorrhagic fever. J Med Virol 2020; 92:2983-2991. [PMID: 32281664 DOI: 10.1002/jmv.25872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 04/08/2020] [Indexed: 12/17/2022]
Abstract
Crimean-Congo hemorrhagic fever (CCHF) is a viral disease. There is not enough knowledge about plasma amino acid levels in CCHF. Therefore, we investigated plasma amino acid levels in patients with CCHF and the association between the levels of these amino acids and disease severity. The plasma amino acid levels (including glutamate [Glu], aspartate [Asp], glutamine [Gln], asparagine [Asn] and gamma-aminobutyric acid [GABA]) in CCHF patients and controls were measured by using liquid chromatography-mass spectrometry. Plasma levels of Gln were lower while Asp, Glu, and GABA levels were higher in patients. In fatal CCHF patients, we found the plasma level of Asn was increased whereas the plasma level of GABA was decreased. This study is the first in the literature to evaluate the plasma Gln, Glu, Asn, Asp, and GABA levels in CCHF patients. We found that the plasma Gln levels were significantly lower in CCHF patients while Asp, Glu, and GABA levels were elevated. Considering that these amino acids are important for immune cells, the plasma amino acid levels of CCHF patients may contribute to the understanding of the pathophysiology of disease and it can be important for supportive treatment of CCHF.
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Affiliation(s)
- Hüseyin Aydin
- Department of Biochemistry, Sivas Cumhuriyet University School of Medicine, Sivas, Turkey
| | - Aynur Engin
- Department of Infectious Diseases and Clinical Microbiology, Sivas Cumhuriyet University School of Medicine, Sivas, Turkey
| | - Sami Keleş
- Ahenk Medical Diagnostic and Research Laboratory, Istanbul, Turkey
| | - Zeynep Ertemur
- Department of Biochemistry, Sivas Cumhuriyet University School of Medicine, Sivas, Turkey
| | - Nezih Hekim
- Department of Molecular Biology and Genetics, Biruni University, School of Medicine and Faculty of Engineering and Natural Sciences, Istanbul, Turkey
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50
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Hirano AA, Vuong HE, Kornmann HL, Schietroma C, Stella SL, Barnes S, Brecha NC. Vesicular Release of GABA by Mammalian Horizontal Cells Mediates Inhibitory Output to Photoreceptors. Front Cell Neurosci 2020; 14:600777. [PMID: 33335476 PMCID: PMC7735995 DOI: 10.3389/fncel.2020.600777] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 11/04/2020] [Indexed: 12/14/2022] Open
Abstract
Feedback inhibition by horizontal cells regulates rod and cone photoreceptor calcium channels that control their release of the neurotransmitter glutamate. This inhibition contributes to synaptic gain control and the formation of the center-surround antagonistic receptive fields passed on to all downstream neurons, which is important for contrast sensitivity and color opponency in vision. In contrast to the plasmalemmal GABA transporter found in non-mammalian horizontal cells, there is evidence that the mechanism by which mammalian horizontal cells inhibit photoreceptors involves the vesicular release of the inhibitory neurotransmitter GABA. Historically, inconsistent findings of GABA and its biosynthetic enzyme, L-glutamate decarboxylase (GAD) in horizontal cells, and the apparent lack of surround response block by GABAergic agents diminished support for GABA's role in feedback inhibition. However, the immunolocalization of the vesicular GABA transporter (VGAT) in the dendritic and axonal endings of horizontal cells that innervate photoreceptor terminals suggested GABA was released via vesicular exocytosis. To test the idea that GABA is released from vesicles, we localized GABA and GAD, multiple SNARE complex proteins, synaptic vesicle proteins, and Cav channels that mediate exocytosis to horizontal cell dendritic tips and axonal terminals. To address the perceived relative paucity of synaptic vesicles in horizontal cell endings, we used conical electron tomography on mouse and guinea pig retinas that revealed small, clear-core vesicles, along with a few clathrin-coated vesicles and endosomes in horizontal cell processes within photoreceptor terminals. Some small-diameter vesicles were adjacent to the plasma membrane and plasma membrane specializations. To assess vesicular release, a functional assay involving incubation of retinal slices in luminal VGAT-C antibodies demonstrated vesicles fused with the membrane in a depolarization- and calcium-dependent manner, and these labeled vesicles can fuse multiple times. Finally, targeted elimination of VGAT in horizontal cells resulted in a loss of tonic, autaptic GABA currents, and of inhibitory feedback modulation of the cone photoreceptor Cai, consistent with the elimination of GABA release from horizontal cell endings. These results in mammalian retina identify the central role of vesicular release of GABA from horizontal cells in the feedback inhibition of photoreceptors.
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Affiliation(s)
- Arlene A. Hirano
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Helen E. Vuong
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Helen L. Kornmann
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Cataldo Schietroma
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Salvatore L. Stella
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Steven Barnes
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Doheny Eye Institute, University of California, Los Angeles, Los Angeles, CA, United States
| | - Nicholas C. Brecha
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA, United States
- Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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