"Activity-Dependent and Projection-Specific Effects of Astrocytes on Plasticity and Memory"
In addition to their well characterized supportive and homeostatic roles, pioneering studies have shown that astrocytes directly affect neuronal activity, supporting the concept of a "tripartite synapse", in which the astrocytes sense and actively modulate synaptic activity and plasticity. In recent years, groundbreaking research revealed many surprising roles for astrocytes in modulating neuronal activity and even behavior. To directly and specifically modulate astrocytic activity we employed a chemogenetic approach: We expressed the Gq-coupled designer receptor hM3Dq or the Gi-coupled designer receptor hM4Di in astrocytes, which allowed their time-restricted activation or inhibition (respectively) by the application of the designer drug clozapine-N-oxide (CNO). We discovered that astrocytic activation is not only necessary for synaptic plasticity, but also sufficient to induce NMDA-dependent de-novo long term potentiation in the hippocampus, which persisted after astrocytic activation ceased. In-vivo, astrocytic activation enhanced memory allocation, i.e. it increased neuronal activity in a task-specific way, only when coupled with learning but not in home-caged mice. Furthermore, astrocytic activation using either chemogenetic or optogenetic tools during acquisition resulted in memory recall enhancement on the following day. Conversely, directly increasing neuronal activity resulted in dramatic memory impairment. Astrocytic inhibition during memory acquisition impairs remote, but not recent, recall. We show that this effect is mediated by a specific disrupting of the projection from the hippocampus to the anterior cingulate cortex by astrocytes. In light of these activity-dependent and projection-specific effects of astrocytes on neuronal function, I will describe new research directions studying the geography and functional significance of hippocampal astrocytic domains, in clear brains and in the CA1 of behaving mice.
Faculty Hosts: Ilana Witten & Elizabeth Gould