Convergent pathways with impaired inhibition at the frontal cortex are the outcome of differential alterations in the male and female schizophrenia model

Schizophrenia is associated with impaired inhibitory neurotransmission and disrupted synaptic plasticity in the medial prefrontal cortex (mPFC), yet the biological mechanisms underlying these deficits may differ between sexes. Here, we used a double-hit rat model, combining perinatal NMDA receptor blockade and post-weaning social isolation, to dissect sex-specific alterations in inhibitory circuit maturation, synaptic plasticity, and prefrontal function. Male double-hit rats exhibited robust schizophrenia-like behaviors, reduced parvalbumin (PV), OTX2, and perineuronal net (PNN) expression, decreased GAD67 levels, and increased DNA damage in PV interneurons, together indicating impaired inhibitory maturation and weakened plasticity. In contrast, females showed milder behavioral deficits but displayed increased PV and OTX2 intensities, enhanced cFos activation in excitatory neurons, and transcriptomic upregulation of glutamatergic, GABAergic, and synapse assembly pathways, suggesting a state of heightened or dysregulated plasticity. Despite these divergent molecular trajectories, in vivo electrophysiology revealed a shared functional endpoint in both sexes: a shift from paired-pulse inhibition to facilitation during basolateral amygdala-evoked responses, reflecting impaired GABAB-mediated inhibitory feedback. Pharmacological blockade of GABAB, but not GABAA, receptors reproduced this phenotype, identifying GABAB signaling as a key mechanism underlying cortical disinhibition. Altogether, our findings reveal that males and females reach convergent prefrontal inhibitory deficits through sex-specific molecular pathways, underscoring the importance of sex as a biological variable in the pathophysiology and treatment of schizophrenia.