Heterogeneous glial regulation of inhibitory hippocampal synapses

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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.