Continuous infusion of neurotrophin-3 triggers sprouting, decreases the levels of TrkA and TrkC, and inhibits epileptogenesis and activity-dependent axonal growth in adult rats.
Neurotrophin-3 (NT-3), a member of the neurotrophin family of neurotrophic factors, is important for cell survival, axonal growth and neuronal plasticity. Epileptiform activation can regulate the expression of neurotrophins, and increases or decreases in neurotrophins can affect both epileptogenesis and seizure-related axonal growth. Interestingly, the expression of nerve growth factor and brain-derived neurotrophic factor is rapidly up-regulated following seizures, while NT-3 mRNA remains unchanged or undergoes a delayed down-regulation, suggesting that NT-3 might have a different function in epileptogenesis. In the present study, we demonstrate that continuous intraventricular infusion of NT-3 in the absence of kindling triggers mossy fiber sprouting in the inner molecular layer of the dentate gyrus and the stratum oriens of the CA3 region. Furthermore, despite this NT-3-related sprouting effect, continuous infusion of NT-3 retards the development of behavioral seizures and inhibits kindling-induced mossy fiber sprouting in the inner molecular layer of the dentate gyrus. We also show that prolonged infusion of NT-3 leads to a decrease in kindling-induced Trk phosphorylation and a down-regulation of the high-affinity Trk receptors, TrkA and TrkC, suggesting an involvement of both cholinergic nerve growth factor receptors and hippocampal NT-3 receptors in these effects. Our results demonstrate an important inhibitory role for NT-3 in seizure development and seizure-related synaptic reorganization.
Xu
B
B
Department of Psychology, McMaster University, L8S 4K1, Hamilton, ON, Canada.
Michalski
B
B
Racine
R J
RJ
Fahnestock
M
M
D000818:Animals; D002452:Cell Count; D003574:Cytochrome c Group / Q000494:pharmacology; D004334:Drug Administration Schedule; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism*; D007696:Kindling, Neurologic / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008970:Molecular Weight; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D019581:Neuropil / Q000166:cytology / Q000187:drug effects; D020933:Neurotrophin 3 / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D020917:Receptor, trkA / Q000187:drug effects / Q000378:metabolism; D020813:Receptor, trkB / Q000187:drug effects / Q000378:metabolism; D020812:Receptor, trkC / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology
D003574:Cytochrome c Group; D020933:Neurotrophin 3; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC