title: Glutamate decarboxylase 67 is expressed in hippocampal mossy fibers of temporal lobe epilepsy patients.
abstract: Recently, expression of glutamate decarboxylase-67 (GAD67), a key enzyme of GABA synthesis, was detected in the otherwise glutamatergic mossy fibers of the rat hippocampus. Synthesis of the enzyme was markedly enhanced after experimentally induced status epilepticus. Here, we investigated the expression of GAD67 protein and mRNA in 44 hippocampal specimens from patients with mesial temporal lobe epilepsy (TLE) using double immunofluorescence histochemistry, immunoblotting, and in situ hybridization. Both in specimens with (n = 37) and without (n = 7) hippocampal sclerosis, GAD67 was highly coexpressed with dynorphin in terminal areas of mossy fibers, including the dentate hilus and the stratum lucidum of sector CA3. In the cases with Ammon's horn sclerosis, also the inner molecular layer of the dentate gyrus contained strong staining for GAD67 immunoreactivity, indicating labeling of mossy fiber terminals that specifically sprout into this area. Double immunofluorescence revealed the colocalization of GAD67 immunoreactivity with the mossy fiber marker dynorphin. The extent of colabeling correlated with the number of seizures experienced by the patients. Furthermore, GAD67 mRNA was found in granule cells of the dentate gyrus. Levels, both of GAD67 mRNA and of GAD67 immunoreactivity were similar in sclerotic and nonsclerotic specimens and appeared to be increased compared to post mortem controls. Provided that the strong expression of GAD67 results in synthesis of GABA in hippocampal mossy fibers this may represent a self-protecting mechanism in TLE. In addition GAD67 expression also may result in conversion of excessive intracellular glutamate to nontoxic GABA within mossy fiber terminals.
authors.affiliation: Department of Pharmacology, Medical University Innsbruck, Austria. guenther.sperk@i-med.ac.at
authors.forename: Günther
authors.initials: G
authors.lastname: Sperk
authors.forename: Anna
authors.initials: A
authors.lastname: Wieselthaler-Hölzl
authors.forename: Susanne
authors.initials: S
authors.lastname: Pirker
authors.forename: Ramon
authors.initials: R
authors.lastname: Tasan
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Strasser
authors.forename: Meinrad
authors.initials: M
authors.lastname: Drexel
authors.forename: Christian
authors.initials: C
authors.lastname: Pifl
authors.forename: Julian
authors.initials: J
authors.lastname: Marschalek
authors.forename: Martin
authors.initials: M
authors.lastname: Ortler
authors.forename: Eugen
authors.initials: E
authors.lastname: Trinka
authors.forename: Katja
authors.initials: K
authors.lastname: Heitmair-Wietzorrek
authors.forename: Philippe
authors.initials: P
authors.lastname: Ciofi
authors.forename: Martha
authors.initials: M
authors.lastname: Feucht
authors.forename: Christoph
authors.initials: C
authors.lastname: Baumgartner
authors.forename: Thomas
authors.initials: T
authors.lastname: Czech
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D018891:Dentate Gyrus / Q000201:enzymology; D004399:Dynorphins / Q000378:metabolism; D004833:Epilepsy, Temporal Lobe / Q000201:enzymology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019599:Mossy Fibers, Hippocampal / Q000201:enzymology*; D009474:Neurons / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005680:gamma-Aminobutyric Acid; D004399:Dynorphins; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1