GABAA RECEPTOR POPULATIONS IN HIPPOCAMPUS AND THALAMUS

海马和丘脑中的 GABAA 受体群

• 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
• 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

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CNS神经元表达GABAA受体（GABAAR），其介导抑制。 GABAAR由5个亚基组成。其中两个是α亚基，两个是β亚基。第五个通常是γ2或δ。 尽管第五个亚基不是门控所必需的，但在重组受体中，γ2或δ亚基的存在 显著改变生物物理和药理学特性。在天然细胞中，第五亚基被认为是 在紧张性（δ亚基）和阶段性（γ2亚基）抑制中起着特殊的作用。我们不明白 由这些亚基定义的受体亚类的生理贡献，尽管新出现的证据 表明受体亚类在精神功能中具有不同的作用，治疗药物靶向一种或多种受体亚类。 另一个亚类产生不同的精神作用。例如，可能具有δ-选择性作用的神经类固醇是新兴的抗抑郁药。不存在将δ受体与γ2受体分开的拮抗剂 受体，所以关于它们各自的贡献仍然存在许多问题。我们被迫 以前方法的缺点和选择性拮抗剂的历史优势，以创建小鼠 在γ2或δ中具有点突变的品系，其赋予对非竞争性GABAAR的抗性 拮抗剂印防己毒素。初步数据显示了这些工具的潜在效用。在这里，我们测试了 假设δ受体介导包括海马在内的皮质区域中δ驱动的去抑制。我们将 探索δ受体在已知表达δ的细胞类别中的作用，这可能为δ驱动的 去抑制最后，我们将测试δ受体在海马和丘脑回路中的影响， 对于神经精神疾病很重要，假设δ驱动的去抑制驱动γ振荡 δ受体负责认知方面，δ受体分别驱动丘脑皮层回路中的睡眠纺锤波。 我们最近的结果已经改变了流行的观点，并允许我们询问受体的作用， 细胞和网络功能的亚群。我们的方法将指导合理的药物开发， 抑制作用