TrkB and Epileptogenesis
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Discovering the cellular and molecular mechanisms underlying the pathophysiology underlying the development of epilepsy is key to the creation of improved treatments. The neurotrophins and their receptors, in particular BDNF and TrkB, are likely candidates to be involved in the process by which a normal brain becomes epileptic (epileptogenesis). The work presented in the dissertation has investigated the hypothesis that TrkB is a central factor in epileptogenesis in multiple animal models of epilepsy.
Conditional deletion of TrkB in the Syn-Cre TrkB-/- mouse prevented nearly all epileptogenesis in the kindling model, despite the ability to have a tonic-clonic seizure. Reduction of TrkB de novo in mature Act-CreER TrkB-/- mice also delayed epileptogenesis in the kindling model. Additionally, Syn-Cre TrkB+/- and Act-CreER TrkB-/- mice had impaired persistence of the hyperexcitable state following kindling. It remained unclear from these findings whether reduction of TrkB during and/or following induction of kindling was responsible for the impaired persistence. The inducible Act-CreER TrkBflox/flox mice were used to reduce TrkB only after the fully kindled state had been reached and demonstrated that loss of TrkB after completion of kindling impairs persistence of the hyperexcitable state.
Status epilepticus is a medical emergency defined by prolonged continuous seizure activity. Conditional deletion of TrkB in the Syn-Cre TrkB-/- mice prevents sustained seizure activity evident in wild type mice following pilocarpine injection. Furthermore, the Syn-Cre TrkB-/- mice may also retain greater sensitivity to diazepam following status epilepticus than control mice. Together with biochemical evidence of TrkB activation during status epilepticus, these findings suggest that TrkB activation is required for persistence of status epilepticus.
In conclusion, the findings in this dissertation demonstrate TrkB to be a molecular mechanism critical for: 1) epileptogenesis in the kindling model; 2) persistence of hyperexcitability in the kindling model; 3) persistence of limbic status epilepticus in a chemoconvulsant model. These discoveries provide the basis for developing novel therapeutic approaches to three distinct and devastating aspects of the limbic epilepsy in humans. These aspects are: 1) preventing progression of limbic epilepsy to a medically refractory state; 2) reversal of medically refractory limbic epilepsy; 3) medically refractory status epilepticus.
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