Collapse of extracellular glutamate regulation during epileptogenesis: down-regulation and functional failure of glutamate transporter function in rats with chronic seizures induced by kainic acid.
We used northern and western blotting to measure the quantity of glutamate and GABA transporters mRNA and their proteins within the hippocampal tissue of rats with epileptogenesis. Chronic seizures were induced by amygdalar injection of kainic acid 60 days before death. We found that expression of the mRNA and protein of the glial glutamate transporters GLAST and GLT-1 were down-regulated in the kainic acid-administered group. In contrast, EAAC-1 and GAT-3 mRNA and their proteins were increased, while GAT-1 mRNA and protein were not changed. We performed in vivo microdialysis in the freely moving state. During the interictal state, the extracellular glutamate concentration was increased, whereas the GABA level was decreased in the kainic acid group. Following potassium-induced depolarization, glutamate overflow was higher and the recovery time to the basal release was prolonged in the kainic acid group relative to controls. Our data suggest that epileptogenesis in rats with kainic acid-induced chronic seizures is associated with the collapse of extracellular glutamate regulation caused by both molecular down-regulation and functional failure of glutamate transport.
Ueda
Y
Y
Department of Psychiatry, Miyazaki Medical College, Miyazaki, Japan. usan@post1.miyazaki-med.ac.jp
Doi
T
T
Tokumaru
J
J
Yokoyama
H
H
Nakajima
A
A
Mitsuyama
Y
Y
Ohya-Nishiguchi
H
H
Kamada
H
H
Willmore
L J
LJ
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D027322:Amino Acid Transport System X-AG; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004827:Epilepsy / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism*; D050485:GABA Plasma Membrane Transport Proteins; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D007608:Kainic Acid; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D011188:Potassium / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D012333:RNA, Messenger; C493415:Slc6a1 protein, rat; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D011188:Potassium; D007608:Kainic Acid