Molecular and Functional Links Between Two Distinct Inhibitory Receptors

Yale University, New Haven CT

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Abstract

PROJECT SUMMARY Inhibitory neurotransmission is of interest for its role in both disease and therapy. Dysregulated inhibitory neurotransmission is implicated in a broad range of psychiatric diseases, such as schizophrenia, anxiety, and autism. Inhibitory receptors are also the target of diverse drugs, including those with clinical utility (benzodiazepines), abuse potential (ethanol), and lethal toxicity (strychnine). Clinical evidence suggests that defects in one inhibitory ionotropic receptor (glycine receptor, or GlyR) can be compensated by boosting activity in a distinct inhibitory ionotropic receptor (GABAA receptor, or GABAAR). The mechanism underlying this clinical phenomenon is not known, which highlights a key gap in our understanding of inhibitory synapses. Both receptors interact with the putative inhibitory scaffold protein, gephyrin, at synaptic sites, but it is unclear how this interaction impacts receptor localization and function. Two independent questions raised by these observations will be addressed here. Aim 1 will establish an in-vivo directional link between GABAAR and GlyR synaptic localization using immunohistochemistry and slice electrophysiology. Aim 2 will reveal the functional impact of gephyrin on GABAAR and GlyR channel properties, surface expression, and assembly in a heterologous system using electrophysiology and biochemistry. A deeper knowledge of the molecular regulation of the inhibitory synapse can change our view of the pathophysiologic basis of devastating psychiatric diseases, and will pave the way for better therapies in the future.