Overview:

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 aimed at prevention of epilepsy or limiting its progression.

Late in the 19th century, an astute British neurologist, William Gowers, proposed that "seizures beget seizures." Gowers had 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 is sufficient to induce development of epilepsy and its progression. 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 pathological 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 promotes the progression of limbic epilepsy. 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). We demonstrated that conditional deletion of TrkB from CNS neurons prevented development of epilepsy in the kindling model (He et al., 2004). TrkB and its downstream signaling pathways is the only 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 seeks to elucidate the signaling pathways activated by TrkB that promote limbic epileptogenesis. Insights into the responsible signaling pathways will provide clues to the structural and functional consequences by which TrkB promotes epileptogenesis. This work centers on the dentate granule cells and their targets, the CA3 pyramidal cells, of hippocampus 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. Work is underway to establish the cellular localization of the activated TrkB and 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 using genetically modified mice to examine the effects of TrkB in additional models of limbic epileptogenesis.

Addressing the questions outlined above will guide efforts aimed at exploiting TrkB as a molecular target for anti-epileptogenic therapies.

Contact 101I Bryan Research Building Box 3209, DUMC 919.668.3896