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.
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BibTeX
@article{fernandezrodrigo2026astrocytic,
title = {{Astrocytic PI3Kα controls synaptic plasticity and cognitive function via serine metabolism}},
author = {Alba Fernández-Rodrigo and Celia García-Vilela and Abel Eraso-Pichot and Irene B Maroto and María D G Moreno and Esperanza López-Merino and Silvia Gutiérrez-Eisman and Carla Sánchez-Castillo and Cristina Boers-Escuder and Eneko Merino-Casamayor and Mariona Graupera and Albert Quintana and María I Cuartero and Maite Solas and Giovanni Marsicano and José A Esteban},
journal = {Nature Communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77319-0},
url = {https://hal.science/hal-05861412v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Astrocytic PI3Kα controls synaptic plasticity and cognitive function via serine metabolism
AU - Alba Fernández-Rodrigo
AU - Celia García-Vilela
AU - Abel Eraso-Pichot
AU - Irene B Maroto
AU - María D G Moreno
AU - Esperanza López-Merino
AU - Silvia Gutiérrez-Eisman
AU - Carla Sánchez-Castillo
AU - Cristina Boers-Escuder
AU - Eneko Merino-Casamayor
AU - Mariona Graupera
AU - Albert Quintana
AU - María I Cuartero
AU - Maite Solas
AU - Giovanni Marsicano
AU - José A Esteban
PY - 2026
DA - 2026/09/04
JO - Nature Communications
DO - 10.1038/s41467-026-77319-0
UR - https://hal.science/hal-05861412v1
AB - 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.
SN - 2041-1723
SN - 2041-1723
ER -