Deciphering the role of neuronal interleukin-1 receptor in early life stress-induced social behavior deficits

Early life stress (ELS) has profound and enduring effects on neurodevelopment and social functioning, contributing to the risk of neurodevelopmental disorders. The interleukin-1 receptor (IL-1R1) in the hippocampus plays a pivotal role in mediating the impact of stress on social behavior. However, the involvement of neuronal IL-1R1 (nIL-1R1) in ELS-induced social deficits remains poorly understood. This study aims to address this gap by utilizing a maternal separation (MS) paradigm and innovative cell-type-specific IL-1R1-expressing mouse lines to elucidate the role of nIL-1R1 in MS-induced long-lasting social interaction deficits. Our investigations revealed dynamic nIL-1R1 expression in the dentate gyrus (DG) during neurodevelopment, particularly within the first two outer granule cell layers from postnatal days 7 to 14. Repeated MS heightens nIL-1R1 and Δ-FosB expression in the DG and induces social interaction abnormalities in adulthood. Further, we found that glutamatergic nIL-1R1 plays a pivotal role in MS-induced neuronal and behavioral alterations. To evaluate whether nIL-1R1 is necessary or sufficient for MS-induced social deficits and decipher nIL-1R1-dependent transcriptomic changes in MS-exposed granule neurons, we assessed social interaction alterations in neonatal IL-1R1 reporter mice and nIL-1R1 expressing mice subjected to MS and employed spatial RNA-Seq (in DG) analysis to identify differential gene expression patterns associated with nIL-1R1 signaling. We seek to gain insights into the molecular mechanisms underlying ELS-induced social behavior difficulties. Unraveling nIL-1R1's role in social behavior deficits holds promise for therapeutic interventions, ultimately improving mental health outcomes for individuals affected by ELS and neurodevelopmental disorders.