The activation of neurotransmitter receptors at synapses mediate synaptic transmission upon being bound by neurotransmitters released from presynaptic terminals. The predominant inhibitory transmitter in the brain is gamma-aminobutyric acid (GABA), and ionotropic GABAA receptors localize at inhibitory synapses to mediate fast inhibitory transmission. Dysregulation of GABA receptors causes various mental and neurological disorders including autism spectrum disorder, schizophrenia, epilepsy, and other disorders. However, precise mechanisms for synaptic localization of GABAA receptors remain unclear. We have recently identified novel GARLH family proteins as a critical regulator of synaptic GABAARs. In this proposal, we aim to reveal in vivo roles of GARLHs in regulating GABAAR activity in the brain, principle rules of GARLH-GABAAR interactions, and molecular relationships of constituents of inhibitory synapses. Successful completion of this proposed work will reveal fundamental molecular mechanisms for determining synaptic localization and transmission of GABAA receptors in the brain. Elucidating the molecular rules governing inhibitory transmission will enable us to identify putative molecular targets for drugs that may alleviate impair neurological and mental disorders.

Public Health Relevance

Dysregulation of GABA receptors in the brain causes various mental and neurological disorders including autism spectrum disorder, schizophrenia, epilepsy, and other disorders. It is critical for human health to establish novel drug targets by revealing molecular constituents of ionotropic GABA receptor complex for controlling brain functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH115705-04
Application #
10056230
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Driscoll, Jamie
Project Start
2017-12-15
Project End
2022-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
4
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Yale University
Department
Physiology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chiu, Chiayu Q; Martenson, James S; Yamazaki, Maya et al. (2018) Input-Specific NMDAR-Dependent Potentiation of Dendritic GABAergic Inhibition. Neuron 97:368-377.e3
Noam, Yoav; Tomita, Susumu (2018) On the Path from Proteomics to Function: GABAAR Trafficking Takes a Turn. Neuron 97:479-481