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. 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.
Authors
- Carla Sánchez‐Castillo (ORCID: https://orcid.org/0000-0002-3697-5825)
- Alba Fernández‐Rodrigo (ORCID: https://orcid.org/0000-0003-3834-0687)
- Mariona Graupera (ORCID: https://orcid.org/0000-0003-4608-4185)
- Irene B. Maroto (ORCID: https://orcid.org/0000-0002-4156-166X)
- Albert Quintana (ORCID: https://orcid.org/0000-0003-1674-7160)
- Celia García-Vilela
- José A. Esteban (ORCID: https://orcid.org/0000-0002-3759-3300)
- Giovanni Marsicano (ORCID: https://orcid.org/0000-0003-3804-1951)
- Silvia Gutiérrez-Eisman
- Maite Solas (ORCID: https://orcid.org/0000-0001-7670-3237)
- Abel Eraso‐Pichot (ORCID: https://orcid.org/0000-0001-6837-2714)
- Esperanza López-Merino (ORCID: https://orcid.org/0009-0004-2265-9858)
- Eneko Merino-Casamayor (ORCID: https://orcid.org/0009-0002-8629-9949)
- Cristina Boers-Escuder
- María I. Cuartero
- María D. G. Moreno (ORCID: https://orcid.org/0009-0002-2033-6612)
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Universidad Complutense de Madrid (ES)
- Universitat Autònoma de Barcelona (ES)
- Université de Bordeaux (FR)
- Inserm (FR)
- Instituto de Salud Carlos III (ES)
- Spanish National Centre for Cardiovascular Research (ES)
- Josep Carreras Leukaemia Research Institute (ES)
- Navarre Institute of Health Research (ES)
- Neurocentre Magendie (FR)
- Centro de Biología Molecular Severo Ochoa (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Universidad Autónoma de Madrid (ES)
- Universidad de Navarra (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-04
- DOI
- https://doi.org/10.1038/s41467-026-77319-0
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fundación Ramón Areces
- Ministerio de Ciencia, Innovación y Universidades
- Centro de Biología Molecular Severo Ochoa
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ministerio de Ciencia e Innovación
- Université de Bordeaux
- Agencia Estatal de Investigación