Heterogeneous glial regulation of inhibitory hippocampal synapses

海马网络由负责整合和长距离通信的主要兴奋性神经元和调节主要细胞活性的局部抑制性中间神经元（IN）组成，特别是生长抑素（SOM）和小清蛋白（PV）中间神经元。此外，星形胶质细胞，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，以调节它们的活性并调节神经元网络中的通信。有趣的是，与IN相似，最近的研究表明星形胶质细胞也显示出异质性。虽然星形胶质细胞调节兴奋性突触活性和可塑性的证据是广泛的，星形胶质细胞在抑制性突触的调节中的作用仍然不明确。我们最近的工作表明，星形胶质细胞差异调节这两个子集的IN突触。因此，我们假设：由于星形胶质细胞的异质性，它们对锥体细胞上不同类型的GABA能突触进行不同的调节，并控制局部网络的兴奋性 我们建议探测抑制性神经元和胶质细胞的子集之间的相互作用，研究星形胶质细胞的差异调节和基本的分子，细胞和网络机制。将有四个目标。 1.我们将研究海马CA1区星形胶质细胞的功能异质性。我们将探讨星形胶质细胞的特性，这些特性选择性地与锥体神经元上的两种抑制性突触相关。 2.我们将测试星形胶质细胞的激活机制是否对抑制性突触的类型具有特异性。我们将使用星形胶质细胞中的Ca2+成像测量和锥体细胞中光遗传学诱发的突触抑制的全细胞记录来确定星形胶质细胞激活的SOM和PV中间神经元选择性机制。 3.我们将使用两种策略研究选择性胶质细胞调节SOM和PV中间神经元特异性突触抑制的影响：1。星形胶质细胞亚群的活性将通过选择性Ca2+螯合或用GDPbS阻断G蛋白活性来阻断。2. DREADD受体将在GFAP启动子的控制下在星形胶质细胞中表达。将测试星形胶质细胞活化对SOM和PV中间神经元在锥体中的光遗传学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IN亚群海马网络活动的影响。我们预测，与SOM突触相关的星形胶质细胞的阻断将影响突触可塑性事件，而阻断与PV突触相关的星形胶质细胞将主要改变海马回路的放电输出。 展望：这项工作将使我们能够解开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。这将为神经元网络的适应性、选择性和整合性胶质调节提供直接证据。

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.