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GABAA RECEPTOR POPULATIONS IN HIPPOCAMPUS AND THALAMUS

海马和丘脑中的 GABAA 受体群

基本信息

批准号：
10220479
负责人：
STEVEN J MENNERICK
金额：
$ 50.01万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10220479
关键词：
Antidepressive Agents Area Behavior Biological Markers Biophysics Cells Clinical Cognition Cytoplasmic Granules Data Disinhibition Dose Drug Receptors Drug Targeting Engineering Epilepsy Frequencies Genes Genetic Glutamate Receptor Goals Hippocampus (Brain)Individual Interneurons Knock-in Knock-out Knowledge Learning Location Mediating Molecular Mood Disorders Moods Mus N-Methylaspartate Neurons Parvalbumins Pharmaceutical Preparations Pharmacology Phase Physiological Picrotoxin Play Point Mutation Population Property Receptor Inhibition Receptor Signaling Recombinants Resistance Role Schizophrenia Signal Transduction Sleep Synapses Technology Testing Thalamic structure Therapeutic Therapeutic Effect base brain health cell type defined contribution delta opioid receptor delta receptors dentate gyrus drug development gamma-Aminobutyric Acid in vivo in vivo evaluation innovation interest kainate mental function neuropsychiatric disorder neuropsychiatry neurosteroids positive allosteric modulator receptor receptor function side effect sleep spindle tool

项目摘要

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.

大多数中枢神经系统神经元表达GABAA受体（GABAARs），介导抑制。