Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model.
Epileptogenesis is the process whereby a normal brain becomes epileptic. We hypothesized that the neurotrophin brain-derived neurotrophic factor (BDNF) activates its receptor, TrkB, in the hippocampus during epileptogenesis and that BDNF-mediated activation of TrkB is required for epileptogenesis. We tested these hypotheses in Synapsin-Cre conditional BDNF(-/-) and TrkB(-/-) mice using the kindling model. Despite marked reductions of BDNF expression, only a modest impairment of epileptogenesis and increased hippocampal TrkB activation were detected in BDNF(-/-) mice. In contrast, reductions of electrophysiological measures and no behavioral evidence of epileptogenesis were detected in TrkB(-/-) mice. Importantly, TrkB(-/-) mice exhibited behavioral endpoints of epileptogenesis, tonic-clonic seizures. Whereas TrkB can be activated, and epileptogenesis develops in BDNF(-/-) mice, the plasticity of epileptogenesis is eliminated in TrkB(-/-) mice. Its requirement for epileptogenesis in kindling implicates TrkB and downstream signaling pathways as attractive molecular targets for drugs for preventing epilepsy.
He
Xiao-Ping
XP
Department of Medicine (Neurology), Duke University Medical Center, Durham, NC 27710, USA.
Kotloski
Robert
R
Nef
Serge
S
Luikart
Bryan W
BW
Parada
Luis F
LF
McNamara
James O
JO
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency / Q000235:genetics*; D004195:Disease Models, Animal; D004597:Electroshock; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D007696:Kindling, Neurologic / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000235:genetics; D010766:Phosphorylation; D020813:Receptor, trkB / Q000172:deficiency / Q000235:genetics*; D012640:Seizures / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB