LAUSR

Abstract Background Social isolation during developmental critical windows could be highly detrimental to proper functioning of mature prefrontal cortex (PFC) and establishment of appropriate adult behaviors. However, the specific circuits that undergo social experience-dependent maturation to regulate social behavior development are poorly understood. Social processing is a domain that is commonly dysregulated in psychiatric disorders including Schizophrenia, and is poorly treated by available psychiatric medications. In humans and rodents, portions of the evolutionarily conserved medial prefrontal cortex (mPFC) are part of a network that regulates social behavior. Many disorders with shared social processing deficits show impairments in inhibitory neurotransmission within the brain, particularly in the mPFC, suggesting a role for PFC inhibitory action in regulating social behavior. Parvalbumin expressing interneurons (PVIs) are one of the major subclasses of inhibitory neurons, implicated in psychiatric disorders. Here we aim to examine a contribution of PVIs in mPFC for social behavior development in mice. Methods We use juvenile social isolation (jSI) during a 2-week sensitive window immediately following weaning and test social behavior in adult mice using the 3-chamber test and reciprocal interaction test. To investigate the causal contribution of mPFC-PVIs in social behavior of adult mice, we leveraged chemogenetic technologies. We selectively expressed hM4Di, an inhibitory DREADD (Designer Receptor Exclusively Activated by Designer Drugs), or hM3Dq an excitatory DREADD in the adult mPFC-PVIs and manipulated mPFC-PVI activity acutely using the selective DREADD agonist, Clozapine-N-oxide (CNO). To test the activity of mPFC-PVIs in response to social experience we used in vivo imaging of calcium transients by fiber photometry. Results We identified a specific activation pattern of parvalbumin-positive interneurons (PVIs) in dorsal-medial PFC (dmPFC) prior to an active bout, or a bout initiated by the focal mouse, but not during a passive bout when mice are explored by a stimulus mouse. Optogenetic and chemogenetic manipulation revealed that brief dmPFC-PVI activation triggers an active social approach to promote sociability. Juvenile social isolation critically decoupled dmPFC-PVI activation from subsequent active social approach by “freezing” the functional maturation process of dmPFC-PVIs during the juvenile-to-adult transition. Chemogenetic activation of dmPFC-PVI activity in the adult animal mitigated juvenile isolation-induced social deficits. Discussion These results demonstrate that PVI development in the juvenile mPFC is critically linked to long-term impacts on social behavior. Our study implicates mPFC PVIs as promising cellular targets for future therapeutic development on social impairments in psychiatric disorders such as Schizophrenia.