PREFRONTAL DISINHIBITION INDUCES SOCIAL AFFECTIVE DEFICITS IN A RAT MODEL OF SCHIZOPHRENIA

Schizophrenia is a serious psychiatric disorder characterized by complex social dysfunctions, including impaired social cognition and empathic abilities. However, effective treatments for these impairments remain elusive due to a limited understanding of their pathology. In this study, we explored the mechanisms underlying social affective deficits in schizophrenia using a rat model.
To establish the model, Sprague-Dawley rat pups were subcutaneously injected with MK-801, an NMDA receptor antagonist, at varying doses (Control: Saline only, Low: 0.2 mg/kg, High: 0.4 mg/kg) twice daily during the neonatal period. Sociability was assessed in adulthood using the Social Affective Preference (SAP) and Social Interaction (SI) tests. These two behavioral paradigms consistently revealed social affective deficits in MK-801-treated rats in a dose-dependent manner.
Given the reported causal relationship between social deficits and cortical disinhibition, particularly in the medial prefrontal cortex (mPFC), we employed the DREADD system to examine whether chemogenetic inhibition could alleviate these social deficits. DREADD-mediated inhibition of the mPFC restored SAP performance in the MK-High group. Histological assessment of the mPFC revealed a decrease in the number of parvalbumin-positive inhibitory neurons, while the overall population of GABAergic neurons remain unaffected in MK-801-treated rats.
This study demonstrates that MK-801-induced rat model of schizophrenia exhibits social affective deficits linked to the dysfunction of parvalbumin-expressing interneurons in the mPFC. We are currently investigating this relationship further from behavioral and neuroscientific perspectives.