Nectin3 on prefrontal excitatory and inhibitory neurons distinctly mediates adolescent stress-induced cognitive and social deficits

Adolescence represents a critical period for prefrontal circuit maturation and heightened vulnerability to stress-related psychopathology. Chronic social defeat stress (CSDS) during adolescence is known to induce enduring cognitive and social deficits, yet the prefrontal molecular mechanisms that mediate these impairments remain poorly understood. Here, we identify the synaptic adhesion molecule nectin3 as a key modulator of adolescent CSDS-induced behavioral dysfunction through cell-type-specific actions in the medial prefrontal cortex (mPFC) of adolescent mice. We first demonstrate that CSDS downregulates nectin3 expression in both excitatory and inhibitory neurons in the mouse mPFC. Genetic knockdown and overexpression manipulations of mPFC nectin3 establish its causal involvement. Crucially, cell-type-specific interventions reveal a double dissociation: nectin3 in excitatory neurons selectively mediates cognitive deficits in temporal order memory and spatial working memory, while nectin3 in inhibitory neurons preferentially regulates social behavior. Structural and electrophysiological measures further revealed that nectin3 knockdown in excitatory (not inhibitory) neurons leads to spine loss and reduced frequency of the miniature excitatory postsynaptic currents in pyramidal neurons, potentially linking nectin3 reduction with cognitive deficits induced by CSDS. These findings reveal cell-specific nectin3 functions underlying different domains of behavioral alterations following adolescent stress, which may serve as potential intervention targets for developing symptom-specific therapeutic strategies against stress-related psychiatric disorders.