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 clarif y whether such convulsive stimulus triggers a long-lasting rearrangement of the neural circuitry culminating in seizure susceptibility, we examined mo lecular, 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 m in and a late prolonged increase on the 10th to 14th day post-EA administra tion, most remarkably in the hippocampus and pyriform cortex. On the 14th d ay 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 additi on, the expression of nerve growth factor (NGF) also showed biphasic increa ses with close spatiotemporal correlation with c-fos expression. Moreover, the number of cell somata and the density of axon fibers of parvalbumin (PA RV)-positive cells, a subpopulation of GABAergic interneurons, decreased in area dentata, CAI 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 seizu res appear to develop seizure susceptibility by causing damage of a subpopu lation of inhibitory interneurons along with increases in the expression of c-fos and NGF in limbic structures. (C) 1999 Elsevier Science B.V. All rig hts reserved.