Glutamate and GABA Transporters in Mesial Temporal Lobe Epilepsy
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AbstractGABA and glutamate transporter proteins are important in relation to epilepsy because they represent the mechanisms that keep the extracellular concentrations of GABA and dicarboxylic amino acids low. GABA and glutamate are the major inhibitory and excitatory neurotransmitters, respectively, in the brain. Consequently, these transporters are major players in enabling the brain to balance inhibition and excitation. In fact, by microdialysis it has been reported changes in extracellular glutamate and GABA levels prior to and during seizures, and it has been postulated that changes in the expression or function of glutamate and GABA transporters may be the cause of the extracellular glutamate excess. Papers 1 and 2 investigate the expression and distribution of GABA transporters (GAT1 and GAT3) and glutamate transporters (GLAST and GLT-1) in the hippocampus from humans with temporal lobe epilepsy (TLE). Epilepsy comprises a heterogeneous group of disorders reflecting underlying brain dysfunction. Temporal lobe epilepsy (TLE) is one of the most common chronic seizure disorders and is the most intensely studied subtype. Temporal lobe epilepsy is divided into mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE), mass-associated temporal lobe epilepsy (MaTLE), and paradoxical temporal lobe epilepsy (PTLE). Hippocampal sclerosis is believed to play a key role in the increased extracellular glutamate concentration and generation of seizures in MTLE. However, it is not known precisely which cell populations, when lost due to sclerosis, cause the network imbalance. As shown in the present thesis, there was no significant overall change in the expression of the main GABA transporters GAT1 and GAT3, but immunohistochemical staining showed regional differences in GAT1 immunoreactivity within the hippocampus. Similarly, the main glutamate transporters, GLAST and GLT-1, showed no overall significant difference in the expression between the non-MTLE and MTLE hippocampi in Paper 2. However, there was a difference in the pattern of immunolabeling for GLAST and GLT- 1. This study does not support the role of glutamate transporters as a cause of elevated levels of extracellular glutamate in the epileptogenic hippocampi, but undetected changes in the splice variants of the transporters or unexpected antibody cross-activity may lead to biased or even false results (Paper 4). In Paper 3 we investigated the glutamate homeostasis in mice lacking the GLT-1 protein. 13C magnetic resonance spectroscopy (MRS) of cortical tissue from GLT-1 knockout mice was performed following intraperitoneal injection of 13C-labeled glucose and acetate. Metabolite levels were analyzed from the neocortex and cerebellum. Compared with wild-type mice, GLT-1 knockout mice had normal levels of glutamate and glutamine in the cerebellum, but they exhibited decreased levels in the neocortex. The findings suggest that GLT-1 in cortical nerve terminals may contribute significantly to the replenishment of the pool of transmitter glutamate thereby short-circuiting the glutamate-glutamine cycle. In conclusion, we did not observe any significant overall changes in the expression of glutamate or GABA transporters in human sclerotic hippocampi, but did observe regional changes. Further, the findings suggesting that GLT-1 in nerve terminals is a major player that needs to be followed up when conditional knockout mice become available. The role of glutamate and GABA transporters in temporal lobe epilepsy remains elusive.
List of papers
|Paper 1 Lee TS, Bjørnsen LP, Paz C, Kim JH, Spencer SS, Spencer DD, et al. GAT1 and GAT3 expression are differently localized in the human epileptogenic hippocampus. Acta Neuropathol. 2006;111(4):351-63. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1007/s00401-005-0017-9|
|Paper 2 Bjørnsen LP, Eid T, Holmseth S, Danbolt NC, Spencer DD, de Lanerolle NC. Changes in glial glutamate transporters in human epileptogenic hippocampus: inadequate explanation for high extracellular glutamate during seizures. Neurobiol Dis. 2007;25(2):319-30. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1016/j.nbd.2006.09.014|
|Paper 3 Bjørnsen LP, Ghezu M, Zhou Y, Danbolt NC, Sonnewald U. The GLT-1 (EAAT2; slc1a2) glutamate transporter is essential for glutamate homeostasis in the neocortex of the mouse. J. Neurochem 2013;128(5):641-649 The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1111/jnc.12509|
|Paper 4 Holmseth S, Dehnes Y, Bjørnsen LP, Boulland JL, Furness DN, Bergles D, et al. Specificity of antibodies: unexpected cross-reactivity of antibodies directed against the excitatory amino acid transporter 3 (EAAT3). Neuroscience. 2005;136(3):649-60. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1016/j.neuroscience.2005.07.022|