Hippocampal neuronal hypoexcitability contributes to PTSD-like phenotypes in the experimental autoimmune encephalomyelitis model

Introduction Patients with multiple sclerosis (MS) frequently exhibit hippocampal atrophy and post-traumatic stress disorder (PTSD)–like symptoms, yet the neural mechanisms linking these clinical features remain unclear. Methods Using the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we employed morphometric analysis, whole-cell recordings, chemogenetic manipulation, and single-nucleus RNA sequencing to investigate the structural, functional, and transcriptional changes in the hippocampus. Results EAE animals recapitulated two core PTSD-relevant phenotypes: impaired fear extinction and contextual fear generalization. Morphometric analysis revealed somatic atrophy of dorsal CA1 pyramidal neurons, and whole-cell recordings demonstrated a marked reduction in firing gain, indicating hippocampal hypoexcitability. Chemogenetic reactivation of CA1 pyramidal neurons ameliorated extinction deficits in EAE mice. Single-nucleus RNA sequencing further revealed a robust neuroimmune-like transcriptional shift in CA1 excitatory neurons, characterized by enrichment of immune/interferon-associated programs (including antigen processing and presentation and MHC-related pathways) together with apoptosis-related gene signatures. Discussion Collectively, these data link neuroinflammation-associated neuronal reprogramming to CA1 structural and functional impairment and suggest that restoring hippocampal excitability may represent a therapeutic avenue for MS patients with comorbid PTSD-like symptoms.