We have developed and characterized an experimental model system of epileptogenesis in mice. In this model, a minimum of 8 generalized seizures initiates two independent pro-epileptogenic processes. One process is rapid, and leads to significant reductions in generalized seizure threshold that are maintained for months. The second process is slowly evolving, and leads to an increase in seizure complexity. This process requires 2-4 weeks to mature, and also is long lasting. We propose to employ this model system to define a role for brain-derived neurotrophic factor (BDNF) in the time-dependent processes leading to increases in seizure susceptibility. The transcription and translation of BDNF has been shown to be significantly regulated by changes in neural activity. The activity-dependent regulation of BDNF in conjunction with the documented ability of BDNF to enhance neural network excitability suggest that BDNF may contribute to the process of epileptogenesis. We hypothesize that repeated, spaced, seizure activity results in progressive increases in BDNF in the CNS. We further hypothesize that increases in BDNF contribute significantly to the increases in seizure susceptibility observed in our experimental model system. To test this hypothesis we propose: (1) to establish the time course of development of increases in seizure susceptibility in mutant mice engineered to either over- or under-express BDNF. If BDNF is involved in the processes that result in increased seizure susceptibility, then the rate at which these processes develop will be predictably increased or decreased in BDNF over- and under-expressors, respectively. (2) to define the magnitude and duration of increases in BDNF protein expression and BDNF-mediated signal transduction during and following repeated seizures in our model. (3) to establish the effects of local, chronic brain infusions of BDNF or BDNF-blocking antibodies on the development of increased seizure susceptibility following repeated seizure activity. Together, the outcome of these studies will define the contribution of BDNF to processes leading to reductions in seizure threshold and to increases in seizure complexity. The experimental model system that serves as the basis for these studies has been characterized in detail. We have defined the minimum requirements for initiating epileptogenic processes in the model, and have defined the temporal characteristics of the processes once initiated. As such, this model system represents a powerful tool for defining a role for BDNF or other factors in epileptogenesis. Finally, the outcome of these studies will contribute new, important information on the ability of repeated seizure activity to affect the regulation, availability and functioning of BDNF in the CNS. These data can serve to direct the development of novel therapeutic strategies designed to alter the availability of BDNF.
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|Mhyre, T R; Applegate, C D (2003) Persistent regional increases in brain-derived neurotrophic factor in the flurothyl model of epileptogenesis are dependent upon the kindling status of the animal. Neuroscience 121:1031-45|
|Ferland, R J; Gross, R A; Applegate, C D (2002) Increased mitotic activity in the dentate gyrus of the hippocampus of adult C57BL/6J mice exposed to the flurothyl kindling model of epileptogenesis. Neuroscience 115:669-83|