Altered expression of brain monocarboxylate transporter 1 in models of temporal lobe epilepsy

TY - JOUR

T1 - Altered expression of brain monocarboxylate transporter 1 in models of temporal lobe epilepsy

AU - Lauritzen, Fredrik

AU - Perez, Edgar L

AU - Melillo, Eric R

AU - Roh, Jung-Min

AU - Zaveri, Hitten P

AU - Lee, Tih-Shih W

AU - Wang, Yue

AU - Bergersen, Linda H

AU - Eid, Tore

N1 - Copyright © 2011 Elsevier Inc. All rights reserved.

PY - 2012/1

Y1 - 2012/1

N2 - Monocarboxylate transporter 1 (MCT1) facilitates the transport of monocarboxylate fuels (lactate, pyruvate and ketone bodies) and acidic drugs, such as valproic acid, across cell membranes. We recently reported that MCT1 is deficient on microvessels in the epileptogenic hippocampal formation in patients with medication-refractory temporal lobe epilepsy (TLE). To further define the role of MCT1 in the pathophysiology of TLE, we used immunohistochemistry and stereological analysis to localize and quantify the transporter in the hippocampal formation in three novel and highly relevant rat models of TLE and in nonepileptic control animals. One model utilizes methionine sulfoximine to induce brain glutamine synthetase deficiency and recurrent limbic seizures, while two models employ an episode of perforant pathway stimulation to cause epilepsy. MCT1 was lost on microvessels and upregulated on astrocytes in the hippocampal formation in all models of TLE. Notably, the loss of MCT1 on microvessels was not due to a reduction in microvessel density. The similarities in MCT1 expression among human subjects with TLE and several animal models of the disease strongly suggest a critical role of this molecule in the pathogenesis of TLE. We hypothesize that the downregulation of MCT1 may promote seizures via impaired uptake of ketone bodies and antiepileptic drugs by the epileptogenic brain. We also propose that the overexpression of MCT1 on astrocytes may lead to increased uptake or release of monocarboxylates by these cells, with important implications for brain metabolism and excitability. These hypotheses can now be rigorously tested in several animal models that replicate key features of human TLE.

AB - Monocarboxylate transporter 1 (MCT1) facilitates the transport of monocarboxylate fuels (lactate, pyruvate and ketone bodies) and acidic drugs, such as valproic acid, across cell membranes. We recently reported that MCT1 is deficient on microvessels in the epileptogenic hippocampal formation in patients with medication-refractory temporal lobe epilepsy (TLE). To further define the role of MCT1 in the pathophysiology of TLE, we used immunohistochemistry and stereological analysis to localize and quantify the transporter in the hippocampal formation in three novel and highly relevant rat models of TLE and in nonepileptic control animals. One model utilizes methionine sulfoximine to induce brain glutamine synthetase deficiency and recurrent limbic seizures, while two models employ an episode of perforant pathway stimulation to cause epilepsy. MCT1 was lost on microvessels and upregulated on astrocytes in the hippocampal formation in all models of TLE. Notably, the loss of MCT1 on microvessels was not due to a reduction in microvessel density. The similarities in MCT1 expression among human subjects with TLE and several animal models of the disease strongly suggest a critical role of this molecule in the pathogenesis of TLE. We hypothesize that the downregulation of MCT1 may promote seizures via impaired uptake of ketone bodies and antiepileptic drugs by the epileptogenic brain. We also propose that the overexpression of MCT1 on astrocytes may lead to increased uptake or release of monocarboxylates by these cells, with important implications for brain metabolism and excitability. These hypotheses can now be rigorously tested in several animal models that replicate key features of human TLE.

KW - Animals

KW - Astrocytes/metabolism

KW - Brain/metabolism

KW - Disease Models, Animal

KW - Epilepsy, Temporal Lobe/genetics

KW - Male

KW - Microvessels/metabolism

KW - Monocarboxylic Acid Transporters/genetics

KW - Rats

KW - Rats, Sprague-Dawley

KW - Symporters/genetics

U2 - 10.1016/j.nbd.2011.08.001

DO - 10.1016/j.nbd.2011.08.001

M3 - Journal article

C2 - 21856423

SN - 0969-9961

VL - 45

SP - 165

EP - 176

JO - Neurobiology of Disease

JF - Neurobiology of Disease

IS - 1

ER -