Astrocytic PI3Kα controls synaptic plasticity and cognitive function via serine metabolism

Abstract

Astrocytes modulate neuronal activity by gliotransmission and through metabolic regulation, yet the relationship between these functions remains poorly understood. Here we show that phosphatidylinositol 3-kinase (PI3K) signaling in astrocytes controls synaptic plasticity and memory by regulating cellular metabolism. Deletion of the p110α isoform of PI3K in hippocampal astrocytes impairs NMDA receptor activation during the induction of hippocampal long-term potentiation (LTP). This defect is rescued by either d-serine (co-agonist of synaptic NMDA receptors) or its precursor l-serine, indicating that PI3K regulates synaptic plasticity through serine availability. Indeed, deletion of p110α rewires astrocyte metabolism, reducing glycolytic flux while enhancing mitochondrial respiration. This, in turn, would limit l-serine biosynthesis through the phosphorylated pathway. Consistently, mice lacking astrocytic p110α display memory deficits that are rescued by in vivo l-serine administration. These findings identify astrocytic PI3K p110α as a key link between cellular metabolism, synaptic plasticity and cognition. The authors find that the PI3Kα pathway links metabolism to hippocampal synaptic plasticity by sustaining astrocyte glycolysis and ensuring L-serine/D-serine supply to neurons. Loss of astrocytic PI3Kα impairs memory in mice, an effect rescued by serine supplementation.