Stress-sensitization of neurons in the dentate gyrus is dependent on neuronal interleukin-1 receptor signaling and is associated with increased synaptic plasticity, perineuronal nets, and excitatory/inhibitory input imbalance.

Repeated social defeat (RSD) in mice causes sensitization of hippocampal neurons associated with enhanced contextual fear memory. Because enhanced fear memory is an integral component of post-traumatic stress disorder, the physiological basis of neuronal sensitization in the hippocampus after social defeat was investigated in male mice using two interventions: microglia depletion (CSF1R antagonist, PLX5622) and neuronal (Vglut2 + ) IL-1R1 -/- mice. Here, two single nuclei (sn) RNAseq data sets using these interventions were integrated and compared. Social defeat altered the transcriptional profiles of CA1 (Satb2 + ), Dentate gyrus (DG, Prox1 + ), and inhibitory (Pval + ) neurons and these stress profiles were influenced by nIL-1R1, microglia, or both. In DG neurons, differentially expressed genes and canonical pathways related to cAMP response element (CREB), calcium/calmodulin kinases, bassoon, and glutamatergic signaling were robustly increased by RSD and these were selectively dependent on nIL-1R1. Based on the snRNAseq data, neuronal stability and plasticity within the hippocampus was assessed. For instance, social defeat increased perineuronal nets around inhibitory (Pval + ) neurons in the DG and these were influenced by both nIL-1R1 and microglia. In addition, RNAscope confirmed that bassoon RNA was amplified after social defeat in the CA1 and DG, and these increases were selectively dependent on nIL-1R1. Last, electrophysiological analyses showed that both spontaneous excitatory and inhibitory postsynaptic current amplitudes in the DG were influenced by social defeat in a nIL-1R1-dependent manner. Collectively, sensitization of dentate gyrus neurons after social defeat requires neuronal IL-1R1 and is associated with enhanced CREB-bassoon signaling and disruption of the excitatory/inhibitory input balance. Significance Statement Traumatic psychological stressors cause “stress-sensitization”, which is represented by an enhanced vulnerability and reactivity to subsequent stressors. Repeated social defeat in mice promotes the convergence of neuronal, neuroinflammatory, and peripheral immune pathways causing anxiety, social avoidance, withdrawal, and stress-sensitization. Sensitization of hippocampal neurons after social defeat is associated with enhanced fear memory and is dependent on neuronal interleukin-1 receptor 1 (nIL-1R1), but independent of microglia. This sensitization with enhanced fear memory is clinically relevant and shares key elements with posttraumatic stress disorder (PTSD). Here, we provided novel findings that sensitization of dentate gyrus neurons after social defeat requires neuronal IL-1R1 and is associated with more perineuronal nets, enhanced CREB-bassoon signaling, and excitatory/inhibitory input imbalance.