Eraso-Pichot, A. | bioRxiv Science

bioRxiv2025

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 p110 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 p110 from hippocampal astrocytes in adult mice, we found that LTP depends on astrocytic p110 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 p110 because of a reduced glycolytic flux. Accordingly, the behavioral impairment in mice lacking p110 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.

neuroscience↗

bioRxiv2023

Distinct endocannabinoids specifically signal to astrocytes and neurons

The endocannabinoid system is an essential intercellular signaling mechanism with a decisive role in many physiological functions of the brain. Endocannabinoids (eCBs), directly acting on presynaptic neuronal CB1 receptors (CB1Rs), can inhibit neurotransmitter release. In addition, they can potentiate adjacent synapses, inducing lateral regulation of synaptic transmission through astrocyte CB1Rs. In contrast to most, if not all, neurotransmitter systems, the eCB system involves two distinct ligands, Anandamide and 2-Arachidonoylglycerol (AEA and 2AG), and a single receptor (CB1R). The physiological meaning of this particularity remains unknown. Here we show that different eCBs are signaling both astrocytes and neurons, inducing distinct and contrasting synaptic regulation. Combining two-photon with a pharmacological and optogenetic approaches and transgenic mice for the synthesis enzyme of both eCBs, we have found that the absence of 2-AG synthesis abolished the inhibitory effect, which was mediated exclusively by neuronal mechanisms. However, the absence of AEA synthesis prevents the lateral potentiation mediated by astrocyte calcium mobilization. Together this indicates that 2-AG signals to neurons, decreasing neurotransmitter release, while AEA signals to astrocytes and induces lateral potentiation. Additionally, AEA synthesis is required for the synaptic potentiation induced by spike-timing-dependent plasticity, as well as astrocyte CB1R, indicating that distinct eCBs-signaling influences neuronal plasticity. We conclude that 2-AG and AEA induce distinct and contrasting synaptic regulation through CB1R in different cell types.

neuroscience↗