Astrocyte Glutamate Uptake and Water Homeostasis Are Dysregulated in the Hippocampus of Multiple Sclerosis Patients With Seizures.
Astrocyte Glutamate Uptake and Water Homeostasis Are Dysregulated in the Hippocampus of Multiple Sclerosis Patients With Seizures.
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DOI：
10.1177/1759091420979604
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发表时间：
2020-01
期刊：
影响因子：
4.7
通讯作者：
Tiwari-Woodruff SK
中科院分区：
文献类型：
--
作者：
Lapato AS;Thompson SM;Parra K;Tiwari-Woodruff SK
虽然癫痫在多发性硬化症（MS）患者中比在总体人群中更为普遍，并且预示着更早的死亡和残疾，但其病因尚不清楚。翻译数据表明，在MS+S小鼠模型中，参与稳态神经元兴奋性的星形细胞分子，包括水通道（AQP4）和突触谷氨酸转运蛋白（EAAT2）的表达受到干扰。然而，MS+S中的星形胶质细胞尚未被检测。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翻译相关性，我们在MS和MS+S供体死后海马中通过免疫组织化学评估脱髓鞘病变负担、星形胶质细胞形成和星形胶质细胞生物标志物（AQP4/EAAT2/连接蛋白cx43）。MS和MS+S组的病变负担相当，但MS+S CA1组星形胶质细胞增生增加，同时EAAT2信号强度降低。AQP4信号在MS+S CA1和CA3中下降，CA1中血管周围AQP4信号缺失。CA3中CX43表达升高。总之，这些数据表明MS+S患者的海马星形胶质细胞在谷氨酸缓冲和水稳态相关分子的表达上存在区域差异，这可能加剧神经元的高兴奋性。重要的是，MS+S中CA1血管周围AQP4的错误定位类似于没有MS病史的癫痫海马，提示趋同病理生理。此外，由于神经病理学集中在MS+S CA1，未来的研究需要确定在脱髓鞘疾病期间癫痫发作的背景下驱动神经胶质功能区域差异的病理生理学。
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.
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影响因子：
6.2
作者：
Fasciani, Ilaria;Pluta, Paula;Barrio, Luis C.
通讯作者：
Barrio, Luis C.
影响因子：
3.5
作者：
Froger, Nicolas;Orellana, Juan A.;Giaume, Christian
通讯作者：
Giaume, Christian
影响因子：
2.2
作者：
Alvestad, Silje;Hammer, Janniche;Ottersen, Ole Petter
通讯作者：
Ottersen, Ole Petter
DOI：
10.1073/pnas.0409308102
发表时间：
2005-01-25
影响因子：
11.1
作者：
Eid, T;Lee, TSW;de Lanerolle, NC
通讯作者：
de Lanerolle, NC
影响因子：
2.4
作者：
GHEZZI, A;MONTANINI, R;CAZZULLO, CL
通讯作者：
CAZZULLO, CL