Search

Elucidating the mechanisms of epileptogenesis in molecular terms can identify targets for therapies aimed at preventing epileptogenesis or limiting its progression. Genetic perturbations have implicated signaling by the neurotrophin, BDNF, and its receptor, TrkB, in limbic epileptogenesis. Whether this signaling is critical to epileptogenesis in the adult brain is unclear. We sought to determine whether reduced expression of TrkB de novo in the mature brain is sufficient to impair epileptogenesis in the kindling model. Treatment of adult Act-CreER TrkB flox/flox mice with tamoxifen resulted in modest reductions of TrkB protein expression de novo in the adult that were detected in hippocampus but not other brain regions. Modest reduction of hippocampal TrkB content inhibited epileptogenesis induced by stimulation of hippocampus or amygdala. The data support the conclusion that reduction of TrkB expression in hippocampus de novo in the mature brain impairs epileptogenesis in the kindling model. These findings advance TrkB and its downstream signaling pathways as attractive targets for limiting the progression of epileptogenesis. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Altered granule cell≫CA3 pyramidal cell synaptic connectivity may contribute to the development of limbic epilepsy. To explore this possibility, granule cell giant mossy fiber bouton plasticity was examined in the kindling and pilocarpine models of epilepsy using green fluorescent protein-expressing transgenic mice. These studies revealed significant increases in the frequency of giant boutons with satellite boutons 2 days and 1 month after pilocarpine status epilepticus, and increases in giant bouton area at 1 month. Similar increases in giant bouton area were observed shortly after kindling. Finally, both models exhibited plasticity of mossy fiber giant bouton filopodia, which contact GABAergic interneurons mediating feedforward inhibition of CA3 pyramids. In the kindling model, however, all changes were fleeting, having resolved by 1 month after the last evoked seizure. Together, these findings demonstrate striking structural plasticity of granule cell mossy fiber synaptic terminal structure in two distinct models of adult limbic epileptogenesis. We suggest that these plasticities modify local connectivities between individual mossy fiber terminals and their targets, inhibitory interneurons, and CA3 pyramidal cells potentially altering the balance of excitation and inhibition during the development of epilepsy. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]