GABAB receptor-mediated regulation of synaptic plasticity in interneurons

GABAB 受体介导的中间神经元突触可塑性调节

• 批准号: 262022631
• 负责人: Professor Dr. Imre Vida
• 金额: --
• 依托单位: Institut für Integrative Neuroanatomie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/262022631?language=en
• 关键词: GABAB; receptor; mediated; regulation; synaptic

The goal of this project is to identify the role of GABAB receptors (GABABRs) in the mediation and modulation of synaptic plasticity in GABAergic inhibitory interneurons (INs). GABABRs act as major regulator of plasticity in principal cells. Although there are multiple sites of action with divergent effects, as a net effect, their activation promotes Hebbian long-term potentiation (LTP) in excitatory principal cell networks. However, INs are highly diverse and their synaptic and intrinsic properties are markedly different to those of principal cells. Therefore GABABRs are expected to have different impact in the various IN types. Consistent with this hypothesis, in the last funding period we found that GABABRs show differential expression and functional effects in pre- and postsynaptic compartments of distinct IN types. We further found that GABABR activation inhibits, rather than facilitates, Hebbian plasticity at excitatory glutamatergic synapses onto somatostatin (SOM)-expressing INs (SOMIs) and parvalbumin (PV)-expressing INs (PVIs). In continuation of this work (1) we aim to investigate the cellular and subcellular distribution of GABABRs in the diverse types of cortical INs in collaboration with TP4 Kulik. (2) We will analyze the cellular and molecular mechanisms underlying the inhibitory effects of GABABRs on synaptic plasticity at excitatory glutamatergic synapses onto INs in close interaction with TP1 Bartos, TP2 Geiger and TP5 Wulff. (3) Investigate the involvement and relevance of GABABR-mediated signalling in functional and structural plasticity of GABAergic output synapses of distinct IN types in collaboration with TP1 Bartos and TP4 Kulik. (4) We will assess whether GABABR-mediated signalling itself can undergo long-term plasticity in INs in parallel to plastic changes at their excitatory inputs in collaboration with TP4 Kulik. Such plasticity could enhance the efficacy and dynamic range of GABABR effects in the control of IN recruitment. Finally, (5) we will develop microcircuit and small-scale network models to analyze the impact of these forms of plasticity for network dynamics in interaction with TP1 Bartos, TP2 Geiger and TP9 Sprekeler. To address these questions we will apply a combination of in vitro electrophysiological, neuroanatomical and computational techniques focusing on two major types of INs, perisomatic-inhibitory PV-positive basket cells (BCs), and dendritic-inhibitory SOM-expressing oriens-lacunosum-moleculare (O-LM) INs. In this project we expect to find cell type- and region specific divergence in the GABABR-mediated modulation of synaptic plasticity and thereby obtain a better understanding of the functional diversity of INs in terms of network state and GABAergic modulation with implications for cognitive functions, as well as disease states of the brain.

本项目的目的是确定GABAB受体（GABABRs）在gaba能抑制性中间神经元（INs）突触可塑性的调解和调节中的作用。GABABRs是主细胞可塑性的主要调节因子。虽然有多个作用位点具有不同的作用，但作为净效应，它们的激活促进了兴奋性主细胞网络中的Hebbian长期增强（LTP）。然而，INs是高度多样化的，它们的突触和内在特性与主细胞明显不同。因此，预计GABABRs在不同的in类型中会产生不同的影响。与这一假设相一致，在上一个资助期内，我们发现GABABRs在不同in类型的突触前和突触后区室中表现出差异表达和功能作用。我们进一步发现，GABABR激活抑制而不是促进兴奋性谷氨酸能突触对表达生长抑素（SOM）的INs （SOMIs）和表达小白蛋白（PV）的INs （PVIs）的Hebbian可塑性。为了继续这项工作(1)，我们的目标是与TP4 Kulik合作，研究GABABRs在不同类型皮质INs中的细胞和亚细胞分布。(2)我们将分析GABABRs与TP1 Bartos、TP2 Geiger和TP5 Wulff密切相互作用，抑制兴奋性谷氨酸突触对INs的突触可塑性的细胞和分子机制。(3)与TP1 Bartos和TP4 Kulik合作，研究gababr介导的信号在不同in类型的gaba能输出突触的功能和结构可塑性中的参与和相关性。(4)我们将与TP4 Kulik合作，评估gababr介导的信号本身是否可以在INs中经历与兴奋性输入的可塑性变化并行的长期可塑性。这种可塑性可以增强GABABR效应控制in招募的有效性和动态范围。最后，(5)我们将开发微电路和小规模网络模型来分析这些形式的可塑性对与TP1 Bartos， TP2 Geiger和TP9 Sprekeler相互作用的网络动力学的影响。为了解决这些问题，我们将结合体外电生理学、神经解剖学和计算技术，重点研究两种主要类型的INs，即周围抑制性pv阳性篮状细胞（BCs）和树突抑制性som表达的定向-空白-分子（O-LM） INs。在这个项目中，我们期望在gababr介导的突触可塑性调节中发现细胞类型和区域特异性的差异，从而更好地了解INs在网络状态和gababr能调节方面的功能多样性，这对认知功能和大脑疾病状态有影响。