A ligand of the p65/p95 receptor suppresses perforant path kindling, kindling-induced mossy fiber sprouting, and hilar area changes in adult rats

Kindling, an animal model of epilepsy, results in an increased volume of the hilus of the dentate gyrus and sprouting of the mossy fiber pathway in the hippocampus. Our previous studies have revealed that chronic infusion of neurotrophins can regulate not only seizure development, but also these kindling-induced structural changes. Kindling, in turn, can alter the expression of neurotrophins and their receptors. We previously showed that intraventricular administration of a synthetic peptide that interferes with nerve growth factor stability and thus its binding to TrkA and p75(NTR) receptors suppressed kindling and sprouting. However, the precise involvement of TrkA, p75(NTR), and downstream signaling effectors of neurotrophins on kindling, sprouting and hilar changes are unknown. One of these downstream effectors is Ras. In the present study, we find that intraventricular infusion of the synthetic peptide Reo3Y, which binds to p65/p95 receptors and causes a rapid inactivation of Ras protein, impairs development of perforant path kindling, reduces the growth in afterdischarge duration, blocks kindling-induced mossy fiber sprouting in area CA3 of hippocampus and in inner molecular layer of the dentate gyrus, and prevents kindling-induced increases in hilar area. These results are consistent with a mediation of neurotrophin effects on kindling, hilar area, and axonal sprouting via Trk receptors, and suggest important roles for Ras in kindling and in kindling-induced structural changes. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.