Molecular regulation of glutamate and GABA transporter proteins by valproic acid in rat hippocampus during epileptogenesis.
Epileptiform discharges and behavioral seizures may be the consequences of the presence of either excessive excitation associated with the neurotransmitter glutamate or from inadequate inhibitory effects associated with gamma-aminobutyric acid (GABA). Synaptic effects of these neurotransmitters are terminated by the action of transporter proteins that remove these amino acids from the synaptic cleft. The glial transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1), and the neuronal transporter excitatory amino acids carrier-1 (EAAC-1) limit excitation initiated by synaptic release of glutamate. Transporter proteins GABA transporter-1 (GAT-1) and GABA transporter-3 (GAT-3) remove GABA from synaptic regions. To assess the molecular effects of the antiepileptic drug valproate, albino rats with chronic, spontaneous, recurrent seizures induced by amygdalar injection of FeCl3 were treated for 14 days with either valproic acid or with saline as an injection control. Regions of the hippocampus were assayed for glutamate and GABA transporters by western blot. While epileptogenesis is thought to correlate with the downregulation of GLAST and upregulation of EAAC-1, valproate caused an increase in the quantity of GLAST protein measured in the hippocampus. Valproate treatment decreased GLT-1 in both control and experimental animals in both hippocampi. EAAC-1 was unchanged by valproate treatment. GABA transporters GAT-1 and GAT-3 in the hippocampus were upregulated by FeCl3 injection into the amygdala. However, valproate caused the downregulation of these GABA transporters in both control and experimental animals. Altered molecular regulation of glutamate appears to be critical in the development of sustained, spontaneous limbic seizures. Our data suggest that valproate may have unique mechanisms of action; specifically, it may affect the removal of glutamate by upregulating GLAST and decreasing GABA transport, which could result in increased tissue concentrations of GABA.
Ueda
Y
Y
Department of Psychiatry, Miyazaki Medical College, Kiyotake, Japan. usan@post1.miyazaki-med.ac.jp
Willmore
L J
LJ
D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000378:metabolism; D027322:Amino Acid Transport System X-AG; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D004827:Epilepsy / Q000139:chemically induced / Q000378:metabolism*; D005296:Ferrous Compounds; D018682:GABA Agents / Q000494:pharmacology*; D050485:GABA Plasma Membrane Transport Proteins; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D000927:Anticonvulsants; D002352:Carrier Proteins; D005296:Ferrous Compounds; D018682:GABA Agents; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; C493415:Slc6a1 protein, rat; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; C029451:ferrous chloride