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Laboratory of James O. McNamara, M.D.MainLab PersonnelRecent Papers


Work in Dr. McNamara's laboratory seeks to elucidate the mechanisms of epileptogenesis, the process by which a normal brain becomes epileptic.  Understanding the mechanisms of epileptogenesis in molecular terms may provide novel targets for pharmacologic interventions for prevention of epilepsy. 

Late in the 19th century, an astute British neurologist, William Gowers, proposed that "seizures beget seizures."  That is, Gowers noted a progressive increase in severity of epilepsy in some of his patients, leading him to postulate that seizures themselves may worsen the epileptic condition and result in unresponsiveness to medication.  Approximately 100 years later, studies of animal models demonstrated that abnormal neuronal activity in the form of focal seizures promotes increased severity of epilepsy.  Thus regardless of the inciting cause, recurrent focal seizures are sufficient to worsen epilepsy, raising the question as to the molecular mechanisms mediating these unwanted effects of neuronal activity. The neurotrophins represent a family of molecules that can link fleeting changes in neuronal activity to long term changes in neuronal structure and function.
We hypothesize that excessive activation of the neurotrophin receptor, TrkB, in the mature brain is required for limbic epileptogenesis. Limbic epileptogenesis is associated with increased expression of the TrkB ligand, brain derived neurotrophic factor (BDNF) and enhanced activation of TrkB in the mossy fiber pathway of hippocampus (Binder et al., 1999a; He et al., 2002; He et al., 2004). Intraventricular infusion of recombinant proteins that scavenge TrkB ligands markedly inhibits epileptogenesis in the kindling model (Binder et al., 1999b). We subsequently demonstrated that conditional deletion of TrkB from CNS neurons markedly inhibited electrophysiological manifestations and prevented all behavioral manifestations of epileptogenesis in the kindling model (He et al., 2004). To the best of our knowledge, TrkB and its downstream signaling pathways is the first pathway found to play an essential role in epileptogenesis in the kindling model. Thus TrkB and its signaling pathways are attractive molecular targets for development of drugs for prevention of epilepsy.
Part of our current work is centered on elucidating the structural and functional consequences of the absence of TrkB that result in prevention of epileptogenesis. This work centers on the dentate granule cells of hippocampus in particular for two reasons. One is the abundant evidence from multiple labs demonstrating that the granule cells normally limit invasion of hippocampus by seizure activity. The second is that we have demonstrated enhanced activation of TrkB in the mossy fiber pathway during epileptogenesis in multiple models; the activated TrkB likely resides in the mossy fiber axons of the granule cells. Work is underway to generate cre recombinase driver lines targeting expression to distinct populations of neurons within the mouse hippocampus. These lines will be crossed to floxed TrkB mice and correlative anatomic and electrophysiological (both in vivo and in vitro) analyses performed to dissect the mechanisms. We are also examining the effects of the conditional deletion of TrkB in additional models of limbic epileptogenesis.  Finally, we are examining the signaling pathways downstream from TrkB that mediate its pro-epileptogenic effects.

Understanding where, when, and how elimination of TrkB prevents epileptogenesis will guide efforts aimed at exploiting TrkB as a molecular target for anti-epileptogenic therapies.

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