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

TY - JOUR

T1 - Evidence for astrocytes as a potential source of the glutamate excess in temporal lobe epilepsy

AU - Perez, Edgar L

AU - Lauritzen, Fredrik

AU - Wang, Yue

AU - Lee, Tih-Shih W

AU - Kang, Dewey

AU - Zaveri, Hitten P

AU - Chaudhry, Farrukh A

AU - Ottersen, Ole P

AU - Bergersen, Linda H

AU - Eid, Tore

N1 - Copyright © 2012 Elsevier Inc. All rights reserved.

PY - 2012/9

Y1 - 2012/9

N2 - 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 10days 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.

AB - 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 10days 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.

KW - Animals

KW - Astrocytes/metabolism

KW - Brain Waves/drug effects

KW - Disease Models, Animal

KW - Electric Stimulation/adverse effects

KW - Electroencephalography

KW - Epilepsy, Temporal Lobe/etiology

KW - Glutamic Acid/metabolism

KW - Hippocampus/metabolism

KW - Male

KW - Methionine Sulfoximine/toxicity

KW - Microscopy, Immunoelectron

KW - Rats

KW - Rats, Sprague-Dawley

U2 - 10.1016/j.nbd.2012.05.010

DO - 10.1016/j.nbd.2012.05.010

M3 - Journal article

C2 - 22659305

SN - 0969-9961

VL - 47

SP - 331

EP - 337

JO - Neurobiology of Disease

JF - Neurobiology of Disease

IS - 3

ER -