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 posttraumatic 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 were 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.