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

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.

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.

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.

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.