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Researchers investigated how blocking NMDA receptors in newborn rats affects social behavior in adulthood, mimicking aspects of schizophrenia. They found that rats treated with the NMDA receptor blocker MK-801 during early development showed impaired social responses as adults, including reduced interest in distressed peers. These social deficits were linked to reduced numbers of parvalbumin-positive inhibitory neurons in the medial prefrontal cortex, and could be reversed by manipulating the activity of specific brain cells in this region.
Why it matters
This study identifies a specific brain circuit mechanism that may contribute to social impairments in schizophrenia, potentially opening new avenues for targeted treatments. Understanding how early developmental disruptions lead to later social dysfunction could help identify at-risk individuals and inform intervention strategies.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.