Long-lasting c-fos and NGF mRNA expressions and loss of perikaryal parvalbumin immunoreactivity in the development of epileptogenesis after ethacrynic acid-induced seizure.
A single cerebroventricular injection of ethacrynic acid (EA), a Cl(-)-ATPase inhibitor, induces generalized tonic-clonic convulsions in mice. To clarify whether such convulsive stimulus triggers a long-lasting rearrangement of the neural circuitry culminating in seizure susceptibility, we examined molecular, cellular and behavioral changes following the EA-induced seizure. The expression of immediate early gene c-fos mRNA as an index for cellular activation increased biphasically, with an early transient increase at 60 min and a late prolonged increase on the 10th to 14th day post-EA administration, most remarkably in the hippocampus and pyriform cortex. On the 14th day post-EA seizure, subconvulsive dose of kainic acid (5-17.5 mg/kg) caused severe (stage 5) seizure in 77% of the mice, with 70% mortality. In addition, the expression of nerve growth factor (NGF) also showed biphasic increases with close spatiotemporal correlation with c-fos expression. Moreover, the number of cell somata and the density of axon fibers of parvalbumin (PARV)-positive cells, a subpopulation of GABAergic interneurons, decreased in area dentata, CA1 and CA3 on the 7th and 14th day post-EA seizure. In area dentata and CA1, the density of glutamic acid decarboxylase (GAD)-positive cells also decreased on the 14th day. Thus, the transient EA-induced seizures appear to develop seizure susceptibility by causing damage of a subpopulation of inhibitory interneurons along with increases in the expression of c-fos and NGF in limbic structures.
Department of Pharmacology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan.
J
J
Suzukawa
K
K
Omori
G
G
Okugawa
Y
Y
Fujiseki
C W
CW
Heizmann
C
C
Inagaki
D000818:Animals; D003292:Convulsants / Q000494:pharmacology; D004198:Disease Susceptibility; D004827:Epilepsy / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004976:Ethacrynic Acid; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics*; D009433:Neural Inhibition / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution / Q000502:physiology
D003292:Convulsants; D018691:Excitatory Amino Acid Antagonists; D009414:Nerve Growth Factors; D010320:Parvalbumins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D004976:Ethacrynic Acid