GABAA RECEPTOR POPULATIONS IN HIPPOCAMPUS AND THALAMUS

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Most CNS neurons express GABAA receptors (GABAARs), which mediate inhibition. GABAARs are comprised of 5 subunits. Two of these are α and two are β subunits. The fifth is usually γ2 or δ. Although the fifth is not required for gating, in recombinant receptors the presence of the γ2 or δ subunit dramatically alters biophysical and pharmacological properties. In native cells, the fifth subunit is thought to mark specific roles in tonic (δ subunit) and phasic (γ2 subunit) inhibition. We do not understand the physiological contributions of receptor subclasses defined by these subunits, although emerging evidence suggests that receptor subclasses have distinct roles in mental functions, and therapeutic drugs target one or the other subclass to produce different psychoactive effects. For instance, neurosteroids, which may have δ-selective actions, are emerging antidepressants. No antagonist exists to separate δ receptors from γ2 receptors, so many questions about their respective contributions remain. We were compelled by the shortcomings of previous approaches and the historical advantages of selective antagonism to create mouse lines with a point mutation in either γ2 or δ, which endows resistance to the non-competitive GABAAR antagonist picrotoxin. Preliminary data show the potential utility of these tools. Here, we test the overarching hypothesis that δ receptors mediate δ-driven disinhibition in cortical areas including the hippocampus. We will explore the role of δ receptors in cell classes known to express δ and that may offer a substrate for δ-driven disinhibition. Finally, we will test the impact of δ receptors in circuits of the hippocampus and thalamus important for neuropsychiatric illness, with the hypothesis that δ-driven disinhibition drives γ oscillations responsible for aspects of cognition, and δ receptors separately drive sleep spindles in thalamocortical circuits. Our recent results have already altered prevailing views and allow us to interrogate roles of receptor subpopulations in cellular and network function. Our approach will guide rational drug development aimed at inhibition.