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Temporal Lobe Epilepsy and the BDNF Receptor, TrkB.

Source

Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012.

Author information

1
Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710
2
Departments of Psychiatry, Physiology & Neuroscience, New York University Langone Medical Center and The Nathan Kline Institute

Excerpt

Temporal lobe epilepsy (TLE) is a particularly devastating form of human epilepsy. The disorder is progressive in a substantial fraction of patients, which is demonstrated by increasing medical intractability, degeneration of cortical tissue, and cognitive impairment. Clinical observations by shrewd clinicians led to the proposal that seizures themselves constitute one factor that promotes worsening of the epileptic condition (1). Availability of animal models in which seizures themselves worsen the epileptic condition provides the opportunity to probe the underlying mechanisms. Insight into the cell surface receptors and downstream signaling pathways that promote epileptogenesis will hopefully provide valuable clues to the cellular mechanisms as well as novel targets for development of therapies aimed at limiting progression. Brain derived neurotrophic factor (BDNF) is a small (14 kD) secreted protein that binds to the ectodomain of its cognate receptor tyrosine kinase, TrkB. Binding of BDNF to TrkB induces receptor dimerization, activation of the receptor tyrosine kinase activity, the phosphorylation of select tyrosines in the cytoplasmic domain creating docking sites for adaptor proteins or enzymes that couple these receptors to intracellular signaling cascades. In diverse animal models of TLE, seizures induce striking increases of BDNF expression and enhanced activation of TrkB in the mossy fiber pathway of hippocampus. Intrahippocampal infusion of BDNF and transgenic overexpression of BDNF or TrkB increase seizure susceptibility or severity. Conditional knockout of TrkB eliminated epileptogenesis altogether in the kindling model. Interestingly, estrogen enhances BDNF expression within hippocampus and treatment of female rats with estrogen led to epileptiform responses of CA3 pyramidal cells to mossy fiber activation, an effect blocked by Trk antagonism. Collectively, these findings establish a causal role for BDNF and TrkB in limbic epileptogenesis and suggest that TrkB signaling may contribute to catamenial epilepsy.

Copyright © 2012, Michael A Rogawski, Antonio V Delgado-Escueta, Jeffrey L Noebels, Massimo Avoli and Richard W Olsen.

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