Genetic inhibition of glutamate allosteric potentiation of GABAARs in mice results in hyperexcitability, leading to neurobehavioral abnormalities
Abstract The imbalance between neuronal excitation and inhibition (E/I) in neural circuit has been considered to be at the root of numerous brain disorders. We recently reported a novel feedback crosstalk between the excitatory neurotransmitter glutamate and inhibitory γ‐aminobutyric acid type A rec...
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| Format: | Article |
| Language: | English |
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Wiley
2023-06-01
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| Series: | MedComm |
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| Online Access: | https://doi.org/10.1002/mco2.235 |
| _version_ | 1797802525345185792 |
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| author | Yehong Du Junjie Li Maoju Wang Qiuyun Tian Yayan Pang Ya Wen Dongchuan Wu Yu Tian Wang Zhifang Dong |
| author_facet | Yehong Du Junjie Li Maoju Wang Qiuyun Tian Yayan Pang Ya Wen Dongchuan Wu Yu Tian Wang Zhifang Dong |
| author_sort | Yehong Du |
| collection | DOAJ |
| description | Abstract The imbalance between neuronal excitation and inhibition (E/I) in neural circuit has been considered to be at the root of numerous brain disorders. We recently reported a novel feedback crosstalk between the excitatory neurotransmitter glutamate and inhibitory γ‐aminobutyric acid type A receptor (GABAAR)‐glutamate allosteric potentiation of GABAAR functions through a direct binding of glutamate to the GABAAR itself. Here, we investigated the physiological significance and pathological implications of this cross‐talk by generating the β3E182G knock‐in (KI) mice. We found that β3E182G KI, while had little effect on basal GABAAR‐mediated synaptic transmission, significantly reduced glutamate potentiation of GABAAR‐mediated responses. These KI mice displayed lower thresholds for noxious stimuli, higher susceptibility to seizures and enhanced hippocampus‐related learning and memory. Additionally, the KI mice exhibited impaired social interactions and decreased anxiety‐like behaviors. Importantly, hippocampal overexpression of wild‐type β3‐containing GABAARs was sufficient to rescue the deficits of glutamate potentiation of GABAAR‐mediated responses, hippocampus‐related behavioral abnormalities of increased epileptic susceptibility, and impaired social interactions. Our data indicate that the novel crosstalk among excitatory glutamate and inhibitory GABAAR functions as a homeostatic mechanism in fine‐tuning neuronal E/I balance, thereby playing an essential role in ensuring normal brain functioning. |
| first_indexed | 2024-03-13T05:07:00Z |
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| id | doaj.art-960e7357f21c40f4979af4b90801540e |
| institution | Directory Open Access Journal |
| issn | 2688-2663 |
| language | English |
| last_indexed | 2024-03-13T05:07:00Z |
| publishDate | 2023-06-01 |
| publisher | Wiley |
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| series | MedComm |
| spelling | doaj.art-960e7357f21c40f4979af4b90801540e2023-06-16T09:40:37ZengWileyMedComm2688-26632023-06-0143n/an/a10.1002/mco2.235Genetic inhibition of glutamate allosteric potentiation of GABAARs in mice results in hyperexcitability, leading to neurobehavioral abnormalitiesYehong Du0Junjie Li1Maoju Wang2Qiuyun Tian3Yayan Pang4Ya Wen5Dongchuan Wu6Yu Tian Wang7Zhifang Dong8Growth, Development, and Mental Health of Children and Adolescence Center Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and Disorders National Clinical Research Center for Child Health and Disorders China International Science and Technology Cooperation Base of Child Development and Critical Disorders Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders Children's Hospital of Chongqing Medical University Chongqing ChinaGrowth, Development, and Mental Health of Children and Adolescence Center Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and Disorders National Clinical Research Center for Child Health and Disorders China International Science and Technology Cooperation Base of Child Development and Critical Disorders Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders Children's Hospital of Chongqing Medical University Chongqing ChinaGrowth, Development, and Mental Health of Children and Adolescence Center Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and Disorders National Clinical Research Center for Child Health and Disorders China International Science and Technology Cooperation Base of Child Development and Critical Disorders Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders Children's Hospital of Chongqing Medical University Chongqing ChinaGrowth, Development, and Mental Health of Children and Adolescence Center Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and Disorders National Clinical Research Center for Child Health and Disorders China International Science and Technology Cooperation Base of Child Development and Critical Disorders Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders Children's Hospital of Chongqing Medical University Chongqing ChinaGrowth, Development, and Mental Health of Children and Adolescence Center Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and Disorders National Clinical Research Center for Child Health and Disorders China International Science and Technology Cooperation Base of Child Development and Critical Disorders Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders Children's Hospital of Chongqing Medical University Chongqing ChinaBrain Research Centre and Department of Medicine Vancouver Coastal Health Research Institute University of British Columbia Vancouver British Columbia CanadaTranslational Medicine Research Center China Medical University Hospital Graduate Institutes of Biomedical Sciences Taichung ChinaBrain Research Centre and Department of Medicine Vancouver Coastal Health Research Institute University of British Columbia Vancouver British Columbia CanadaGrowth, Development, and Mental Health of Children and Adolescence Center Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and Disorders National Clinical Research Center for Child Health and Disorders China International Science and Technology Cooperation Base of Child Development and Critical Disorders Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders Children's Hospital of Chongqing Medical University Chongqing ChinaAbstract The imbalance between neuronal excitation and inhibition (E/I) in neural circuit has been considered to be at the root of numerous brain disorders. We recently reported a novel feedback crosstalk between the excitatory neurotransmitter glutamate and inhibitory γ‐aminobutyric acid type A receptor (GABAAR)‐glutamate allosteric potentiation of GABAAR functions through a direct binding of glutamate to the GABAAR itself. Here, we investigated the physiological significance and pathological implications of this cross‐talk by generating the β3E182G knock‐in (KI) mice. We found that β3E182G KI, while had little effect on basal GABAAR‐mediated synaptic transmission, significantly reduced glutamate potentiation of GABAAR‐mediated responses. These KI mice displayed lower thresholds for noxious stimuli, higher susceptibility to seizures and enhanced hippocampus‐related learning and memory. Additionally, the KI mice exhibited impaired social interactions and decreased anxiety‐like behaviors. Importantly, hippocampal overexpression of wild‐type β3‐containing GABAARs was sufficient to rescue the deficits of glutamate potentiation of GABAAR‐mediated responses, hippocampus‐related behavioral abnormalities of increased epileptic susceptibility, and impaired social interactions. Our data indicate that the novel crosstalk among excitatory glutamate and inhibitory GABAAR functions as a homeostatic mechanism in fine‐tuning neuronal E/I balance, thereby playing an essential role in ensuring normal brain functioning.https://doi.org/10.1002/mco2.235epilepsyexcitation‐inhibition balanceGABAA receptorsynaptic transmission |
| spellingShingle | Yehong Du Junjie Li Maoju Wang Qiuyun Tian Yayan Pang Ya Wen Dongchuan Wu Yu Tian Wang Zhifang Dong Genetic inhibition of glutamate allosteric potentiation of GABAARs in mice results in hyperexcitability, leading to neurobehavioral abnormalities MedComm epilepsy excitation‐inhibition balance GABAA receptor synaptic transmission |
| title | Genetic inhibition of glutamate allosteric potentiation of GABAARs in mice results in hyperexcitability, leading to neurobehavioral abnormalities |
| title_full | Genetic inhibition of glutamate allosteric potentiation of GABAARs in mice results in hyperexcitability, leading to neurobehavioral abnormalities |
| title_fullStr | Genetic inhibition of glutamate allosteric potentiation of GABAARs in mice results in hyperexcitability, leading to neurobehavioral abnormalities |
| title_full_unstemmed | Genetic inhibition of glutamate allosteric potentiation of GABAARs in mice results in hyperexcitability, leading to neurobehavioral abnormalities |
| title_short | Genetic inhibition of glutamate allosteric potentiation of GABAARs in mice results in hyperexcitability, leading to neurobehavioral abnormalities |
| title_sort | genetic inhibition of glutamate allosteric potentiation of gabaars in mice results in hyperexcitability leading to neurobehavioral abnormalities |
| topic | epilepsy excitation‐inhibition balance GABAA receptor synaptic transmission |
| url | https://doi.org/10.1002/mco2.235 |
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