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<p>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.</p><p>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.</p><p>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.</p><p>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.</p>
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