Heterogeneous glial regulation of inhibitory hippocampal synapses

抑制性海马突触的异质胶质调节

• 批准号: RGPIN-2020-05264
• 负责人: Robitaille, Richard
• 金额: $ 5.03万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=717358
• 关键词: Heterogeneous; glial; regulation; inhibitory; hippocampal

The hippocampal network is composed of principal excitatory neurons responsible for integration and long distance communication, and local inhibitory interneurons (IN) that regulate the activity of principal cells, in particular the somatostatin (SOM) and parvalbumin (PV) interneurons. In addition, astrocytes, the main glial cells in the CNS, interact with excitatory and inhibitory neurons to regulate their activity and tune communication in the neuronal network. Interestingly, similar to IN, recent work revealed that astrocytes also show heterogeneity. While evidence of astrocyte modulation of excitatory synapses activity and plasticity is extensive, the roles of astrocytes in the regulation of inhibitory synapses remains ill defined. Our recent work suggests that astrocytes differentially regulate these two subsets of IN synapses. Hence, we hypothesize that: Owing to their heterogeneity, astrocytes differentially regulate distinct types of GABAergic synapses on pyramidal cells and control local networks excitability We propose to probe interactions between subsets of inhibitory neurons and glial cells, to study the differential regulation of astrocytes and the underlying fundamental molecular, cellular and network mechanisms. Four objectives will be targeted. 1. We will examine the functional heterogeneity of astrocytes in CA1 area of hippocampus. We will characterise the properties of astrocytes that are selectively associated with the two types of inhibitory synapses on pyramidal neurons. 2. We will test if the mechanisms of activation of astrocytes are specific to the types of inhibitory synapses. We will use Ca2+ imaging measurements in astrocytes and whole cell recordings of optogenetically-evoked synaptic inhibition in pyramidal cells to determine the SOM and PV interneuron selective mechanisms of astrocyte activation. 3. We will study the impact of the selective glial regulation of SOM and PV interneuron specific synaptic inhibition using two strategies: 1. Activity of the subpopulation of astrocytes will be blocked by selective Ca2+ chelating or G-protein activity blockade with GDPbS. 2. DREADD receptors will be expressed in astrocytes under the control of a GFAP promoter. Effects of astrocyte activation on the optogenetically-evoked synaptic inhibition in pyramidal by SOM and PV interneurons will be tested. 4. We will examine the impact of astrocyte regulation on hippocampal network activity on subset of IN. We predict that blockade of astrocytes associated with SOM synapses will influence synaptic plasticity events while blocking those associated with PV synapses will mainly alter the firing output of the hippocampal circuit. Perspectives: This work would allow us to unravel a functional heterogeneity of hippocampal astrocytes and its role in the hippocampal network. This would provide direct evidence of adaptive, selective and integrated glial regulation of a neuronal network.

海马网络由负责整合和长距离通信的主要兴奋性神经元以及调节主要细胞活性的局部抑制性中间神经元（IN），尤其是生长抑素（SOM）和Parvalbumin（PV）中间神经元。此外，星形胶质细胞是中枢神经系统中的主要神经胶质细胞，与兴奋性和抑制性神经元相互作用，以调节其活性并调节神经元网络中的通信。有趣的是，类似于最近的工作表明，星形胶质细胞也显示出异质性。 尽管兴奋性突触活动和可塑性的星形胶质细胞调节的证据是广泛的，但星形胶质细胞在抑制突触调节中的作用仍然不明显。 我们最近的工作表明，星形胶质细胞差异地调节了这两个子集的突触。 因此，我们假设： 由于其异质性，星形胶质细胞在金字塔细胞上差异化了不同类型的GABA能突触，并控制局部网络的兴奋性 我们建议探测抑制性神经元和神经胶质细胞的子集之间的相互作用，以研究星形胶质细胞的差异调节以及基本的基本分子，细胞和网络机制。将针对四个目标。 1。我们将检查海马CA1区域星形胶质细胞的功能异质性。我们将表征与锥体神经元上两种类型的抑制突触相关的星形胶质细胞的特性。 2。我们将测试星形胶质细胞激活的机制是否特定于抑制性突触的类型。我们将在星形胶质细胞中使用CA2+成像测量值，并在金字塔细胞中光遗传诱发的突触抑制的全细胞记录中确定星形胶质细胞激活的SOM和PV Interneuron选择性机制。 3。我们将使用两种策略研究SOM和PV间神经元特异性突触抑制的选择性神经胶质调节的影响：1。星形胶质细胞亚群的活性将通过使用GDPB的选择性Ca2+螯合或G蛋白活性阻断来阻止。 2。Dreadd受体将在GFAP启动子的控制下以星形胶质细胞表示。将测试星形胶质细胞激活对SOM和PV中间神经元在金字塔中的光源性诱发的突触抑制的影响。 4。我们将研究星形胶质细胞调节对海马网络活动对IN子集的影响。我们预测，与SOM突触相关的星形胶质细胞的封锁将影响突触可塑性事件，而阻止与PV突触相关的星形胶质细胞将主要改变海马电路的发射输出。 观点：这项工作将使我们能够揭示海马星形胶质细胞的功能异质性及其在海马网络中的作用。这将提供神经元网络的自适应，选择性和综合的神经胶质调节的直接证据。