Frontiers in psychiatry · 2026
Hippocampal neuronal hypoexcitability contributes to PTSD-like phenotypes in the experimental autoimmune encephalomyelitis model.
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Zhong Xinghua, Zhang Han, Xie Jieying, Gao Yang, Wang Honghao, Peng Yu, Yi Feng, Chen Jinyu
Аннотация
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.
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.