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.