Social isolation disrupts prefrontal excitatory-inhibitory balance to impair social novelty memory in adult male mice.

Social isolation is a pervasive stressor that disrupts social cognition, yet its neural mechanisms in adulthood remain unclear. Here, we showed that four weeks of social isolation in adult male mice selectively impaired social novelty memory without affecting general sociability, object recognition, working memory, or anxiety- and depression-like behaviors. This deficit was sex-specific, as female mice remained unaffected. Mechanistically, c-Fos mapping and in vivo calcium imaging revealed that social isolation induced a maladaptive shift in prefrontal excitatory-inhibitory (E/I) balance, characterized by both exaggerated activation of medial prefrontal cortex (mPFC) glutamatergic neurons and attenuated recruitment of local GABAergic interneurons specifically during novel social exploration. Causal manipulations showed that chemogenetic or optogenetic activation of mPFC glutamatergic neurons in group-housed males was sufficient to recapitulate the social novelty memory impairment, whereas inhibition of these neurons in isolated mice rescued the deficit. At the cellular level, electrophysiological recordings demonstrated that SI enhanced the intrinsic excitability of mPFC pyramidal neurons and induced a synaptic E/I imbalance, characterized by increased excitatory and decreased inhibitory drive. Together, our findings establish that adult social isolation disrupts social novelty memory processing by shifting the mPFC excitatory-inhibitory balance toward a net hyperexcitable state, revealing a reversible, circuit-specific mechanism for isolation-induced social cognitive deficits.