Reduced astroglial-synapse coverage on cortical non-engram cells shapes remote memory strength.

Astrocytes and neuronal synapses function as bidirectional partners in the modulation of synaptic transmission, and remodeling of perisynaptic astrocytic processes (PAPs) in the hippocampus gates the strength of recent fear memory. Whether cortical PAP remodeling contributes to remote memory consolidation, and whether this is different between synapses of engram versus non-engram neurons, is elusive. Here, we present Astro-GRASP, a genetically targeted approach to investigate astrocyte-synapse interactions. In the prelimbic cortex (PL), fear conditioning (FC) globally increases astrocyte-synapse coverage during recent memory consolidation, whereas astrocytes selectively retract from non-engram synapses at a remote time point after learning. Ezrin depletion from astrocytes reduces local astrocyte-synapse coverage and enhances remote memory expression, confirming the functional relevance of astroglial interaction with cortical synapses. Together, our findings indicate that astrocyte-synapse coverage on PL non-engram, rather than engram neurons, shapes remote memory strength, highlighting a previously unrecognized role for astrocytic remodeling of memory consolidation in cortical circuitry.