Astrocytic PI3Kα controls synaptic plasticity and cognitive function via serine metabolism

Astrocytes are known to modulate neuronal activity by gliotransmission and through metabolic regulation. However, the connection between these two processes is still poorly defined. In this work we show that the p110α isoform of the phosphatidylinositol 3-kinase (PI3K) in astrocytes is required for long-term potentiation (LTP) and has an impact on learning and memory. Using a specific deletion of p110α from hippocampal astrocytes in adult mice, we found that LTP depends on astrocytic p110α to sustain D-serine levels for the activation of NMDA receptors during LTP induction. This requirement is based on the L-serine biosynthetic pathway of the astrocyte, which is defective in the absence of p110α because of a reduced glycolytic flux. Accordingly, the behavioral impairment in mice lacking p110α can be rescued by in vivo administration of L-serine. These results link for the first time the function of PI3K in astrocytes to cerebral metabolism and its influence in synaptic plasticity and cognition.