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

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 

作者机构：DM Centre for Brain Health and Department of MedicineVancouver Coastal Health Research InstituteUniversity of British ColumbiaVancouverBCV6T 2B5Canada Pediatric Research InstituteMinistry 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 InstitueShanghaiTech UniversityShanghaiP.R.China 

出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)

年 卷 期：2022年第7卷第11期

页      面：4156-4173页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 100204[医学-神经病学] 10[医学] 

基　　金：Canadian Institutes of Health Research(CIHR),Taiwan National Science Council(NSC 102–2320-B-039–038-MY3) Ministry of Science and Technology(MOST 104-2320-B-039-045-MY3,MOST107-2320-B039-060-MY3,MOST 107-2320-B-039-061-MY3,MOST 110-2320-B-039-010-MY3,and MOST 111-2321-B-A49-005-),China Medical University(CMU-107-Z-01,CMU108-MF-14) National Natural Science Foundation of China(82071395,82001158,32170959) Natural Science Foundation of Chongqing(cstc2020jcyj-zdxmX0004 and cstc2021ycjh-bgzxm0186) Science and Technology Research Program of Chongqing Municipal Education Commission(KJZD-K201900403) Innovation Research Group at Institutions of Higher Education in Chongqing(CXQTP19034) CQMU Program for Youth Innovation in Future Medicine(No.W0044). 

主　　题：excitation thereby maintained 

摘      要：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 illnesses.Here we identify a novel glutamate-GABAAR interaction mediated by a direct glutamate binding of the GABAAR.In HEK293 cells overexpressing recombinant GABAARs,glutamate and its analog ligands,while producing no current on their own,potentiate GABA-evoked currents.This potentiation is mediated by a direct binding at a novel glutamate binding pocket located at theα+/β−subunit interface of the GABAAR.Moreover,the potentiation does not require the presence of aγsubunit,and in fact,the presence ofγsubunit significantly reduces the potency of the glutamate potentiation.In 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 currents.Most 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 susceptibility.These results demonstrate a novel cross-talk between excitatory transmitter glutamate and inhibitory GABAAR.Such 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.