Revealing distinct mechanisms and functions of neuronal inhibition in vivo

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Summary/Abstract Communication between neurons within and across brain regions is essential for proper brain function. This communication is mediated by neuronal excitability, which is tightly controlled by neuronal inhibition. GABAARs play an essential role in mediating neuronal inhibition, and dysregulation in GABAAR activity has been implicated in a variety of disorders, including autism, epilepsy and schizophrenia. GABAARs mediate inhibitory synaptic transmission through two distinct mechanisms, phasic and tonic inhibition. While phasic inhibition is fast and localized at synapses, tonic inhibition is persistent and spreads throughout the dendrite and the cell body. Despite the importance of phasic and tonic inhibition in controlling neuronal excitability, little is known about their distinct roles in vivo. This is due to difficulty in eliminating one type of inhibition without affecting the other. The subunit composition of the GABAARs that mediate phasic and tonic inhibition is highly redundant. GARLHs are auxiliary subunits that control the synaptic localization of GABAARs, without affecting their surface expression. In the present study, I aim to reveal the distinct roles of phasic and tonic inhibition in vivo by making use of a cell-specific GARLH knockout mouse, where phasic inhibition has been abolished without alterations in tonic inhibition. Furthermore, I have found that both phasic and tonic inhibition are abolished in a novel conditional triple knockout mice of GABAAR β1/2/3. By contrasting the behavioral performance and the cell biology of synapses between these two knockout mice, I will be able to discern the specific roles of phasic and tonic inhibition in motor behavior and in the formation and stability of synaptic circuits. Successful completion of this proposal will reveal critical roles for synaptic and extrasynaptic GABAARs in the synaptic architecture of neurons, and motor behavior. It will also reveal novel molecules responsible for the synaptic localization of GABAARs in the adult brain. Combined, these results will provide valuable insight in our understanding of inhibitory neurotransmission in the brain, and help identify key therapeutic targets for motor disorders.