Grant: Project Grant

The A-type g-aminobutyric acid receptor (GABAAR) is the principal receptor mediating inhibitory synaptic transmission in the brain. It counteracts glutamatergic excitatory synaptic transmission and thus plays a critical role in maintaining the proper excitability of neurons. GABAAR dysfunction leads to abnormal neuronal excitability and contributes to the pathogenesis of many brain disorders, such as epileptic encephalopathy, developmental delay, and mental illnesses. Thus, elucidating the mechanisms regulating GABAAR function is fundamental for our better understanding of how our brain functions normally and dysfunctions pathologically, and is also essential for developing more effective drugs to treat brain disorders. Therefore, the main research aim of our application is to investigate the mechanisms regulating GABAAR function, and we will realize the research aim by carrying out the following two projects. First, we will extend our recent discovery that the excitatory transmitter glutamate directly binds to and potentiates GABAAR function by further studying the underlying mechanism of this novel excitatory and inhibitory cross-talk, and its contribution to brain function and dysfunction. Through our characterization, we hope to develop novel therapeutics for treating brain disorders caused by the hypo-functioning of GABAARs. Second, we will continue our clinically originated studies of pathogenic de nova GABAAR mutations. Particularly, we will investigate how some gain-of-function mutations we unexpectedly discovered from epilepsy patients contribute to the pathogenesis of epilepsy and delayed cognitive development, thereby screening effective drugs to treat these patients. The proposed research will not only further uncover mechanistic elements of the GABAAR regulation in brain function and dysfunction but may also lead to the development of novel therapeutics for treating brain disorders caused by these receptor dysfunctions.