Evidence for astrocytes as a potential source of the glutamate excess in temporal lobe epilepsy

Neurobiology of Disease

Tih-Shih W. Lee¹  Yue Wang²  Tore Eid³  Linda H. Bergersen⁴  Fredrik Lauritzen⁵  Edgar L. Perez⁵  Ole P. Ottersen⁶  Farrukh A. Chaudhry⁷  Dewey Kang⁷  Hitten P. Zaveri⁸ 

[1] Brain and Muscle Energy Group, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway;Centre for Molecular Biology and Neuroscience, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway;The Biotechnology Centre of Oslo, Oslo, Norway;Centre for Molecular Biology and Neuroscience, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway;Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA;Department of Neurology, Yale University School of Medicine, New Haven, CT, USA;Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA;Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA;

关键词: Animal models;    Excitotoxicity;    Glutamine synthetase;    Hippocampal sclerosis;    Methionine sulfoximine;   

DOI  :  

来源: DOAJ

【 摘 要 】

Increased extracellular brain glutamate has been implicated in the pathophysiology of human refractory temporal lobe epilepsy (TLE), but the cause of the excessive glutamate is unknown. Prior studies by us and others have shown that the glutamate degrading enzyme glutamine synthetase (GS) is deficient in astrocytes in the epileptogenic hippocampal formation in a subset of patients with TLE. We have postulated that the loss of GS in TLE leads to increased glutamate in astrocytes with elevated concentrations of extracellular glutamate and recurrent seizures as the ultimate end-points. Here we test the hypothesis that the deficiency in GS leads to increased glutamate in astrocytes. Rats were chronically infused with methionine sulfoximine (MSO, n=4) into the hippocampal formation to induce GS deficiency and recurrent seizures. A separate group of rats was infused with 0.9% NaCl (saline) as a control (n=6). At least 10 days after the start of infusion, once recurrent seizures were established in the MSO-treated rats, the concentration of glutamate was assessed in CA1 of the hippocampal formation by immunogold electron microscopy. The concentration of glutamate was 47% higher in astrocytes in the MSO-treated vs. saline-treated rats (p=0.02), and the ratio of glutamate in astrocytes relative to axon terminals was increased by 74% in the MSO-treated rats (p=0.003). These data support our hypothesis that a deficiency in GS leads to increased glutamate in astrocytes. We additionally propose that the GS-deficient astrocytes in the hippocampal formation in TLE lead to elevated extracellular brain glutamate either through decreased clearance of extracellular glutamate or excessive release of glutamate into the extracellular space from these cells, or a combination of the two.

【 授权许可】

Unknown