Dysregulation of gamma-aminobutyric acid (GABA) mediated neurotransmission has been implicated in neuropsychiatric disorders including epilepsy, anxiety disorder and schizophrenia. Furthermore, GABA type A receptors (GABAARs), a diverse group of hetero-pentameric ion channels, are the target of both clinically relevant and abused drugs, such as benzodiazepines, barbiturates, inhaled anesthetics and ethanol. To mediate inhibitory GABAegic neuro-transmission in the brain, GABAARs must localize at postsynapses. Yet, the mechanisms controlling synaptic localization of GABAAR in the brain remain poorly understood. The proposed study aims to identify the domain within the GABAAR pentamer that mediates synaptic targeting. Currently, a prominent model in the field is that the 2 GABAAR subunit mediates synaptic localization, which is supported by loss of synaptic GABAAR activity in primary cortical cultured neurons from the 2 knockout mice. However, a deficit in synaptic GABAAR activity may result from deficits in assembly, surface expression, protein stabilization, synaptic targeting or changes in channel properties. Importanty, my preliminary analysis of a 2 subunit conditional knockout mouse indicates that the 2 subunit is not the subunit mediating synaptic localization of GABAARs. Therefore, the proposed study aims to 1) elucidate the precise role of the 2 subunit in the brain and 2) identify the minimal domain(s) necessary and sufficient for synaptic localization, but dispensable for subunit stability, assembly and surface expression. To address these aims, knockout and overexpression approaches, respectively, will be used. Successful completion of this proposal will provide me not only with novel findings regarding GABAARs, but also various experimental techniques and knowledge, and thus is an ideal proposal for the F30 training program.
Dysregulation of gamma-aminobutyric acid (GABA) mediated synaptic transmission has been implicated in neuropsychiatric disorders including epilepsy, anxiety disorder and schizophrenia. Furthermore, GABA type A receptors (GABAARs), a diverse group of hetero-pentameric ion channels, are the target of both clinically relevant and abused drugs, such as benzodiazepines, barbiturates, inhaled anesthetics and ethanol. This study will provide insight into how synaptic GABAAR activity in the brain is regulated in both health and disease.
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|Martenson, James S; Tomita, Susumu (2015) Synaptic localization of neurotransmitter receptors: comparing mechanisms for AMPA and GABAA receptors. Curr Opin Pharmacol 20:102-8|