ASTROCYTIC PI3K SPECIFICALLY REGULATES ASTROCYTE-TO-NEURON COMMUNICATION DURING LONG-TERM SYNAPTIC DEPRESSION, WITH CONSEQUENCES FOR COGNITIVE PERFORMANCE

Activity-dependent synaptic plasticity supports brain function and cognitive performance. NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. Phosphatidylinositol 3-kinase (PI3K) signaling in neurons is a key regulator of synaptic plasticity mechanisms involving both long-term potentiation (LTP) and LTD. Altered activity of PI3K and its downstream mediators are related to synaptic dysfunction and diverse cognitive disorders. However, the specific contributions of PI3K in the astrocyte for synaptic plasticity and cognition remain virtually unexplored. Previously, we had demonstrated that LTD at CA3-CA1 synapses is driven by astrocyte-to-neuron communication via glutamate release from astrocytes acting on neuronal NMDA receptors. Here we show that specific deletion of type I PI3K catalytic isoform p110β in astrocytes abolishes NMDA receptor-dependent LTD expression and astrocyte-to-neuron communication mediated by glutamate. Accordingly, mice lacking astrocytic PI3K-p110β showed impaired spatial and social memory performance. NMDA receptor-dependent LTD in PI3K-p110β -depleted astrocytes is rescued by optogenetically activating astrocytic calcium signaling. Ongoing experiments will address the precise molecular mechanism that defines PI3K signaling as a regulatory hub integrating the bidirectional communication between astrocytes and neurons to modulate synaptic plasticity in the hippocampus.