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Glutamate and GABAA receptor crosstalk mediates homeostatic regulation of neuronal excitation in the mammalian brain

引用

Signal Transduction and Targeted Therapy 2022年第11期7卷 4156-4173页

作者： Ya Wen Zhifang Dong Jun Liu Peter Axerio-Cilies Yehong Du Junjie Li Long Chen Lu Zhang Lidong Liu Jie Lu Ning Zhou Dong Chuan Wu Yu Tian Wang DM Centre for Brain Health and Department of Medicine Vancouver Coastal Health Research InstituteUniversity of British ColumbiaVancouverBCV6T 2B5Canada Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChina International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory DisordersChildren’s Hospital of Chongqing Medical UniversityChongqing400014P.R.China ihuman institue ShanghaiTech UniversityShanghaiP.R.China

Maintaining a proper balance between the glutamate receptor-mediated neuronal excitation and the A type of GABA receptor(GABAAR)mediated inhibition is essential for brain functioning;and its imbalance contributes to the pathogenesis of many brain disorders including neurodegenerative diseases and mental *** we identify a novel glutamate-GABAAR interaction mediated by a direct glutamate binding of the *** HEK293 cells overexpressing recombinant GABAARs,glutamate and its analog ligands,while producing no current on their own,potentiate GABA-evoked *** potentiation is mediated by a direct binding at a novel glutamate binding pocket located at theα+/β−subunit interface of the ***,the potentiation does not require the presence of aγsubunit,and in fact,the presence ofγsubunit significantly reduces the potency of the glutamate *** addition,the glutamate-mediated allosteric potentiation occurs on native GABAARs in rat neurons maintained in culture,as evidenced by the potentiation of GABAAR-mediated inhibitory postsynaptic currents and tonic *** importantly,we found that genetic impairment of this glutamate potentiation in knock-in mice resulted in phenotypes of increased neuronal excitability,including decreased thresholds to noxious stimuli and increased seizure *** results demonstrate a novel cross-talk between excitatory transmitter glutamate and inhibitory *** a rapid and short feedback loop between the two principal excitatory and inhibitory neurotransmission systems may play a critical homeostatic role in fine-tuning the excitation-inhibition balance(E/I balance),thereby maintaining neuronal excitability in the mammalian brain under both physiological and pathological conditions.

关键词： excitation thereby maintained

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