While seizure disorders are more prevalent among multiple sclerosis (MS) patients than the population overall and prognosticate earlier death & disability, their etiology remains unclear. Translational data indicate perturbed expression of astrocytic molecules contributing to homeostatic neuronal excitability, including water channels (AQP4) and synaptic glutamate transporters (EAAT2), in a mouse model of MS with seizures (MS+S). However, astrocytes in MS+S have not been examined. To assess the translational relevance of astrocyte dysfunction observed in a mouse model of MS+S, demyelinated lesion burden, astrogliosis, and astrocytic biomarkers (AQP4/EAAT2/ connexin-CX43) were evaluated by immunohistochemistry in postmortem hippocampi from MS & MS+S donors. Lesion burden was comparable in MS & MS+S cohorts, but astrogliosis was elevated in MS+S CA1 with a concomitant decrease in EAAT2 signal intensity. AQP4 signal declined in MS+S CA1 & CA3 with a loss of perivascular AQP4 in CA1. CX43 expression was increased in CA3. Together, these data suggest that hippocampal astrocytes from MS+S patients display regional differences in expression of molecules associated with glutamate buffering and water homeostasis that could exacerbate neuronal hyperexcitability. Importantly, mislocalization of CA1 perivascular AQP4 seen in MS+S is analogous to epileptic hippocampi without a history of MS, suggesting convergent pathophysiology. Furthermore, as neuropathology was concentrated in MS+S CA1, future study is warranted to determine the pathophysiology driving regional differences in glial function in the context of seizures during demyelinating disease.

虽然癫痫症在多发性硬化症 (MS) 患者中比总体人群更普遍，并且预示着早期死亡和残疾，但其病因尚不清楚。转化数据表明，在癫痫发作 (MS+S) 的 MS 小鼠模型中，星形胶质细胞分子的表达受到干扰，这些分子有助于稳态神经元兴奋性，包括水通道 (AQP4) 和突触谷氨酸转运蛋白 (EAAT2)。然而，尚未检查 MS+S 中的星形胶质细胞。为了评估在 MS+S 小鼠模型中观察到的星形胶质细胞功能障碍的转化相关性，脱髓鞘病变负荷、星形胶质细胞增生和星形胶质细胞生物标志物（AQP4/EAAT2/连接蛋白-CX43）通过免疫组织化学在来自 MS 和 MS+S 供体的死后海马中进行评估. MS 和 MS+S 队列中的病变负担相当，但星形胶质细胞增生在 MS+S CA1 中升高，同时 EAAT2 信号强度降低。MS+S CA1 和 CA3 中 AQP4 信号下降，CA1 中血管周围 AQP4 丢失。CA3 中 CX43 表达增加。总之，这些数据表明来自 MS+S 患者的海马星形胶质细胞在与谷氨酸缓冲和水稳态相关的分子表达方面表现出区域差异，这可能会加剧神经元过度兴奋。重要的是，在 MS+S 中看到的 CA1 血管周围 AQP4 的错误定位类似于没有 MS 病史的癫痫海马，表明会聚病理生理学。此外，由于神经病理学集中在 MS+S CA1，未来的研究有必要确定在脱髓鞘疾病期间癫痫发作的情况下驱动神经胶质功能区域差异的病理生理学。