Neonatal NMDA receptor blockade disrupts prefrontal cortical regulation of social affective behavior: implications for schizophrenia

Abstract

Developmental N-methyl-D-aspartate receptor (NMDAr) hypofunction has been implicated in the pathophysiology of schizophrenia, including cognitive and emotional deficits. However, the neural circuit mechanisms linking developmental NMDAr hypofunction to social affective impairments remain poorly understood. Here, we investigated schizophrenia-related social affective dysfunction induced by neonatal exposure to the NMDAr antagonist MK-801 and examined the contribution of the medial prefrontal cortex (mPFC), a key hub for socio-cognitive function. Sprague-Dawley rat pups received subcutaneous injections of saline or MK-801 (MK-Low: 0.2 mg/kg; MK-High: 0.4 mg/kg) during the neonatal period. In adulthood, social affective behaviors were assessed using the Social Affective Preference (SAP) and Social Interaction (SI) tests. MK-801-treated rats, particularly the MK-High group, displayed impaired social affective responses, characterized by reduced preference for and investigation of distressed conspecifics. These impairments were ameliorated by chemogenetic inhibition of pyramidal cells in the mPFC, whereas activation of these neurons disrupted social affective behavior in naive rats. Histological analyses revealed reduced parvalbumin-positive interneuron (PVIN) density in the mPFC of MK-801-treated rats. Consistent with the involvement of PVIN dysfunction, selective activation of mPFC PVINs alleviated social affective deficits in MK-801-treated rats. These findings identify impaired PVIN-mediated inhibitory regulation within the mPFC as a circuit mechanism underlying social affective dysfunction following neonatal NMDAr blockade, providing insight into the pathophysiology of schizophrenia-related social impairments.