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.
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Department of Psychiatry and Behavioral Neurosciences, McMaster University, 1200 Main Street West, ON, L8N 3Z5, Hamilton, Canada.
Uri Saragovi
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Racine
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Fahnestock
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D000818:Animals; D002135:Calcium-Binding Proteins; D002452:Cell Count; D018797:Cell Cycle Proteins; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000378:metabolism* / Q000503:physiopathology; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology*; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism*; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D019580:Perforant Pathway / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D050863:Synaptotagmin I; D050857:Synaptotagmins; D014764:Viral Proteins; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; C400208:Reo3Y protein, Mammalian orthoreovirus 3; D050863:Synaptotagmin I; D014764:Viral Proteins; D050857:Synaptotagmins; D020794:Receptor Protein-Tyrosine Kinases; D018631:ras Proteins