KCC2 was downregulated in small neurons localized in epileptogenic human focal cortical dysplasia.
Focal cortical dysplasia (FCD), which is characterized histologically by disorganized cortical lamination and large abnormal cells, is one of the major causes of intractable epilepsies. γ-aminobutyric acid (GABA)(A) receptor-mediated synchronous depolarizing potentials have been observed in FCD tissue. Since alterations in Cl(-) homeostasis might underlie these depolarizing actions of GABA, cation-Cl(-) cotransporters could play critical roles in the generation of these abnormal actions. We examined the expression patterns of NKCC1 and KCC2 by in situ hybridization histochemistry and immunohistochemistry in FCD tissue obtained by surgery from patients with intractable epilepsy. KCC2 mRNA and protein were expressed not only in non-dysplastic neurons in histologically normal portions located in the periphery of the excised cortex, but also in dysplastic cells in FCD tissue. The levels of KCC2 mRNA and protein were significantly decreased in the neurons around large abnormal neurons (giant neurons), but not in giant neurons, compared with non-dysplastic neurons. The neurons localized only around giant neurons significantly smaller than non-dysplastic neurons. However NKCC1 expression did not differ among these cell types. These results suggest that the intracellular Cl(-) concentration ([Cl(-)](i)) of small neurons might increase, so that depolarizing GABA actions could occur in the FCD tissue of epileptic foci.
Department of Physiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan. shimizuc@kph.bunri-u.ac.jp
Chigusa
C
Shimizu-Okabe
Masaki
M
Tanaka
Kazumi
K
Matsuda
Tadahiro
T
Mihara
Akihito
A
Okabe
Kohji
K
Sato
Yushi
Y
Inoue
Tateki
T
Fujiwara
Kazuichi
K
Yagi
Atsuo
A
Fukuda
D000328:Adult; D002648:Child; D002712:Chlorides / Q000378:metabolism; D015536:Down-Regulation; D004351:Drug Resistance; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000145:classification / Q000378:metabolism* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D028021:Sodium-Potassium-Chloride Symporters / Q000096:biosynthesis / Q000235:genetics; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters / Q000096:biosynthesis* / Q000235:genetics*; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000096922:K Cl- Cotransporters
D002712:Chlorides; D012333:RNA, Messenger; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C578877:SLC12A2 protein, human