Astrocytic facilitation of somatic NMDARs underpins hippocampal E-S potentiation

Abstract

EPSP–spike (E-S) potentiation is a form of plasticity defined by a persistent increase in neuronal spike output for a given synaptic input, reflecting enhanced E-S coupling independent of synaptic strength. However, its cellular mechanisms remain poorly understood. Here, we show that brief induction of E-S potentiation triggers a sustained calcium activity increase in astrocytes adjacent to the hippocampal CA1 pyramidal layer. Mechanistically, E-S potentiation critically requires GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) localized to the neuronal soma. Sustained astrocytic activity promotes E-S potentiation through vesicular release of D-serine, which enhances tonic activation of somatic NMDARs, suppresses A-type potassium currents, and produces a lasting increase in neuronal excitability. Functionally, this astrocyte-dependent E-S potentiation lowers the threshold for subsequent long-term potentiation, conferring a metaplastic influence on hippocampal circuits. These findings identify an astrocyte-neuron signaling mechanism that drives intrinsic plasticity and establish somatic NMDARs as a key site of astrocytic regulation of hippocampal output.