Astrocytic PI3Kα controls synaptic plasticity and cognitive function via serine metabolism

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. We thank the members of the Esteban laboratory for critical reading of the manuscript and the personnel at the fluorescence microscopy facility (SMOA), the electron microscopy facility, and the animal house of the CBM for expert technical assistance.

Cuezva and his team for the technical guidance on the extracellular lactate measurements protocol. We also thank Cristina García-Cáceres and her team for technical advice on the glucose uptake assay protocol. We thank Susana Cadenas, too, for performing the first Oroboros trials with total hippocampal homogenates.

Finally, we thank Antonio C. Pagano Zottola for the technical support in the Oroboros experiments with isolated mitochondria and Ignacio Fernández-Moncada for his technical advice for the iGlucoSnFR sensor. This work was supported by the Spanish Ministry of Science, Innovation and Universities grants PID2020-117651RB, PDC2021-120815-I00, and PID2023-149056OB-I00 to J.A.E., PID2020-114977RB-I00 and PID2023-151947OB-I00 to A.Q., PID2021-128737NB-I00 to M.S., and RYC2022-037937-I to M.I.C.

This work was also supported by Inserm, the European Research Council (Micabra, ERC-2017-AdG-786467), Fondation pour la Recherche Medicale (DRM20101220445), the Human Frontiers Science Program, Region Aquitaine, the French State/Agence Nationale de la Recherche (ERA-Net Neuron CanShank ANR-21-NEU2-0001-04, CaMeLS ANR-23-CE16-0022-01, Hippobese ANR-23-CE14-0004-03) and the French government in the framework of the University of Bordeaux’s IdEx “Investments for the Future - France 2030” program/GPR BRAIN_2030 to G.M. The Spanish Ministry of Science and Innovation supported A.F.-R., E.L.-M., C.G.-V., C.S.-C., and M.D.G.M. with predoctoral contracts, and I.B.M with a “Juan de la Cierva” postdoctoral contract. A.E.-P. was supported by Région Nouvelle Aquitaine: Convention AAPR2022-2021-16762910.