Differential expression of alpha1, alpha2, alpha3, and alpha5 GABAA receptor subunits in seizure-prone and seizure-resistant rat models of temporal lobe epilepsy.
Temporal lobe epilepsy remains one of the most widespread seizure disorders in man, the etiology of which is controversial. Using new rat models of temporal lobe epilepsy that are either prone or resistant to develop complex partial seizures, we provide evidence that this seizure susceptibility may arise from arrested development of the GABAA receptor system. In seizure-prone (Fast kindling) and seizure-resistant (Slow kindling) rat models, both the mRNA and protein levels of the major alpha subunit expressed in adult brain (alpha1), as well as those highly expressed during development (alpha2, alpha3, and alpha5), were differentially expressed in both models compared with normal controls. We found that alpha1 subunit mRNA expression in the Fast kindling strain was approximately half the abundance of control rats, whereas in the Slow kindling strain, it was approximately 70% greater than that of controls. However, Fast rats overexpressed the alpha2, alpha3, and alpha5 ("embryonic") subunits, having a density 50-70% greater than controls depending on brain area, whereas the converse was true of Slow rats. Using subunit-specific antibodies to alpha1 and alpha5 subunits, quantitative immunoblots and immunocytochemistry revealed a concordance with the mRNA levels. alpha1 protein expression was approximately 50% less than controls in the Fast strain, whereas it was 200% greater in the Slow strain. In contrast, alpha5 subunit protein expression was greater in the Fast strain than either the control or Slow strain. These data suggest that a major predispositional factor in the development of temporal lobe epilepsy could be a failure to complete the normal switch from the GABAA receptor alpha subunits highly expressed during development (alpha2, alpha3, and alpha5) to those highly expressed in adulthood (alpha1).
Poulter
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MO
Laboratory of Molecular Neuropharmacology, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, K1A 0R6.
Brown
L A
LA
Tynan
S
S
Willick
G
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William
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R
McIntyre
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DC
D000818:Animals; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007696:Kindling, Neurologic; D010446:Peptide Fragments / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics*; D012640:Seizures / Q000378:metabolism*
D010446:Peptide Fragments; D012333:RNA, Messenger; D011963:Receptors, GABA-A