Transient Inhibition of TrkB Kinase after Status Epilepticus Prevents Development of Temporal Lobe Epilepsy

Abstract

Temporal lobe epilepsy is the most common and often devastating form of human epilepsy. The molecular mechanism underlying the development of temporal lobe epilepsy remains largely unknown. Emerging evidence suggests that activation of the BDNF receptor TrkB promotes epileptogenesis caused by status epilepticus. We investigated a mouse model in which a brief episode of status epilepticus results in chronic recurrent seizures, anxiety-like behavior, and destruction of hippocampal neurons. We used a chemical-genetic approach to selectively inhibit activation of TrkB. We demonstrate that inhibition of TrkB commencing after status epilepticus and continued for 2weeks prevents recurrent seizures, ameliorates anxiety-like behavior, and limits loss of hippocampal neurons when tested weeks to months later. That transient inhibition commencing after status epilepticus can prevent these long-lasting devastating consequences establishes TrkB signaling as an attractive target for developing preventive treatments of epilepsy in humans

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Published Version (Please cite this version)

10.1016/j.neuron.2013.04.027

Publication Info

Liu, Gumei, Bin Gu, Xiao-Ping He, Rasesh B Joshi, Harold D Wackerle, Ramona Marie Rodriguiz, William C Wetsel, James O McNamara, et al. (2013). Transient Inhibition of TrkB Kinase after Status Epilepticus Prevents Development of Temporal Lobe Epilepsy. Neuron, 79(1). pp. 31–38. 10.1016/j.neuron.2013.04.027 Retrieved from https://hdl.handle.net/10161/11840.

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Scholars@Duke

Wetsel

William Christopher Wetsel

Associate Professor in Psychiatry and Behavioral Sciences

RESEARCH INTERESTS
Last Updated: 27 October 2020

My laboratory uses genetically-modified mice to study the roles that certain genes and gene products play in the presentation of abnormal neuroendocrine, neurological, and psychiatric responses. Traditionally, the identification of neuroendocrine dysfunction has involved biochemical analyses of hormonal responses, those for neurological disorders have relied upon behavioral and postmortem analyses, and those for psychiatric conditions have depended upon phenomenology.  The use of genetic technologies has allowed specific genes in selected cells and in neural pathways to be related to certain molecular, biochemical, cellular, physiological, and behavioral dysfunctions. As the Director of the Mouse Behavioral and Neuroendocrine Analysis Core Facility at Duke University (http://sites.duke.edu/mousebehavioralcore/), we have phenotyped many different lines of inbred and mutant mice for my own work as well as for investigators at Duke and at other research institutions. As a consequence, we have helped to develop many different mouse genetic models of neuroendocrine and neuropsychiatric illness. We are working also with academic medicinal chemists and/or certain pharmacological/biotechnological companies to identify novel compounds that will ameliorate abnormal responses in various mutant mouse models. Some of these preclinical studies have formed a basis for clinical trials in humans.

McNamara

James O'Connell McNamara

Duke School of Medicine Distinguished Professor in Neuroscience

Our goal is to elucidate the cellular and molecular mechanisms underlying epileptogenesis, the process by which a normal brain becomes epileptic.  The epilepsies constitute a group of common, serious neurological disorders, among which temporal lobe epilepsy (TLE) is the most prevalent and devastating. Many patients with severe TLE experienced an episode of prolonged seizures (status epilepticus, SE) years prior to the onset of TLE. Because induction of SE alone is sufficient to induce TLE in diverse mammalian species, the occurrence of de novo SE is thought to contribute to development of TLE in humans.  Elucidating the molecular mechanisms by which an episode of SE induces lifelong TLE in an animal model will provide targets for preventive and/or disease modifying therapies.   Using a chemical-genetic method, we discovered a molecular mechanism required for induction of TLE by an episode of SE, namely, the excessive activation of the BDNF receptor tyrosine kinase, TrkB (Liu et al., 2013).  We subsequently discovered that phospholipase Cg1 is the dominant signaling effector by which excessive activation of TrkB promotes epilepsy (Gu et al., 2015).  We designed a novel peptide (pY816) that uncouples TrkB from phospholipase Cg1.  Treatment with pY816 following status epilepticus prevented TLE (Gu et al., 2015).  In addition to prevention, we have now shown that partial reversal of  epileptogenesis with pY816(Krishnamurthy et al., 2019), raising the possibility of ameliorating TLE after it has developed.   Collectively, these findings provide proof-of-concept evidence for a novel strategy targeting receptor tyrosine kinase signaling and identify a novel therapeutic for prevention and disease modification of TLE.   

 

There are two major objectives of our current work.    1.  We are developing peptide and small molecule inhibitors of TrkB signaling for advancement to the clinic. 2.  We seek to understand the cellular consequences of TrkB activation that transform the brain from normal to epileptic.  We have identified the sites within hippocampus at which SE-induced activation of TrkB occurs (Helgager et al 2013).  One is the spines of apical dendrites of CA1 pyramidal cells.  We are utilizing an in vitro model in which we mimic the enhanced synaptic release of glutamate during SE.  Using two photon uncaging microscopy, exquisitely localized high concentrations of glutamate are generated over a spine of an apical dendrite of a CA1 pyramidal cell in cultured hippocampus, resulting in long term potentiation. We have developed novel sensors to dynamically image activation of TrkB within a single spine. We have discovered that induction of long term potentiation requires activation of TrkB, mediated in part by uncaging induced release of BDNF from the same spine (Harward et al 2016).  This provides a valuable model with which to elucidate the mechanisms mediating activation of TrkB and the downstream signaling pathways by which its activation promotes long term potentiation (Hedrick et al 2016).

 

Helgager J, Liu G, McNamara JO.  The cellular and synaptic location of activated TrkB in mouse hippocampus during limbic epileptogenesis. J Comp Neurol. 521(3):499-521. 2013. (PMCID: PMC3527653)

Liu, G., Gu, B, He, X., Joshi, R.B., Wackerle, H.D., Rodriguiz, R.M., Wetsel, W.C., and McNamara, J.O. Transient Inhibition of TrkB Kinase after Status Epilepticus Prevents Development of Temporal Lobe Epilepsy. Neuron 79:31-38, 2013. (PMCID: PMC3744583).*

Gu, B., Huang,  Yang Zhong Huang, He, Xiao-Ping He, Joshi, R. B., Jang, Wonjo,  & McNamara, J.O.  A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cγ1 Prevents Epilepsy Induced by Status Epilepticus.  Neuron 88(3):484-491, 2015.  PMID:26481038. PMCID: pending

Harward, S. C., Hedrick, N. G., Hall, C. E., Parra-bueno, P., Milner, T. A., Pan, E., … Yasuda, R., McNamara J.O. (2016). Autocrine BDNF-TrkB signalling within a single dendritic spine, 13–16. doi:10.1038/nature19766

Hedrick, N. G., Harward, S. C., Hall, C. E., Murakoshi, H., McNamara, J. O., & Yasuda, R. (2016). Rho GTPase complementation underlies BDNF-dependent homo- and heterosynaptic plasticity. Nature. doi:10.1038/nature19784

Krishnamurthy K, Huang YZ, Harward SC, Sharma KK, Tamayo DL, McNamara J.O.  Regression of Epileptogenesis by Inhibiting Tropomyosin B Signaling Following a Seizure. Annals of Neurology 86(6): 939-950, 2019.

 

Our publications can be found at: http://www.ncbi.nlm.nih.gov/sites/myncbi/1rMG926fr2ikx/bibliography/48320844/public/?sort=date&direction=ascending


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