TrkB-Shc Signaling Protects against Hippocampal Injury Following Status Epilepticus.

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Temporal lobe epilepsy (TLE) is a common and commonly devastating form of human epilepsy for which only symptomatic therapy is available. One cause of TLE is an episode of de novo prolonged seizures [status epilepticus (SE)]. Understanding the molecular signaling mechanisms by which SE transforms a brain from normal to epileptic may reveal novel targets for preventive and disease-modifying therapies. SE-induced activation of the BDNF receptor tyrosine kinase, TrkB, is one signaling pathway by which SE induces TLE. Although activation of TrkB signaling promotes development of epilepsy in this context, it also reduces SE-induced neuronal death. This led us to hypothesize that distinct signaling pathways downstream of TrkB mediate the desirable (neuroprotective) and undesirable (epileptogenesis) consequences. We subsequently demonstrated that TrkB-mediated activation of phospholipase Cγ1 is required for epileptogenesis. Here we tested the hypothesis that the TrkB-Shc-Akt signaling pathway mediates the neuroprotective consequences of TrkB activation following SE. We studied measures of molecular signaling and cell death in a model of SE in mice of both sexes, including wild-type and TrkBShc/Shc mutant mice in which a point mutation (Y515F) of TrkB prevents the binding of Shc to activated TrkB kinase. Genetic disruption of TrkB-Shc signaling had no effect on severity of SE yet partially inhibited activation of the prosurvival adaptor protein Akt. Importantly, genetic disruption of TrkB-Shc signaling exacerbated hippocampal neuronal death induced by SE. We conclude that therapies targeting TrkB signaling for preventing epilepsy should spare TrkB-Shc-Akt signaling and thereby preserve the neuroprotective benefits.SIGNIFICANCE STATEMENT Temporal lobe epilepsy (TLE) is a common and devastating form of human epilepsy that lacks preventive therapies. Understanding the molecular signaling mechanisms underlying the development of TLE may identify novel therapeutic targets. BDNF signaling thru TrkB receptor tyrosine kinase is one molecular mechanism promoting TLE. We previously discovered that TrkB-mediated activation of phospholipase Cγ1 promotes epileptogenesis. Here we reveal that TrkB-mediated activation of Akt protects against hippocampal neuronal death in vivo following status epilepticus. These findings strengthen the evidence that desirable and undesirable consequences of status epilepticus-induced TrkB activation are mediated by distinct signaling pathways downstream of this receptor. These results provide a strong rationale for a novel therapeutic strategy selectively targeting individual signaling pathways downstream of TrkB for preventing epilepsy.





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Huang, Yang Zhong, Xiao-Ping He, Kamesh Krishnamurthy and James O McNamara (2019). TrkB-Shc Signaling Protects against Hippocampal Injury Following Status Epilepticus. The Journal of neuroscience : the official journal of the Society for Neuroscience, 39(23). pp. 4624–4630. 10.1523/jneurosci.2939-18.2019 Retrieved from

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Yangzhong Huang

Assistant Research Professor of Neurobiology

The goal of my research is to elucidate the molecular and signaling mechanisms underlying epilepsy, a common and commonly devastating neurological disorder. There are two major objectives of my current work. I aim to understand the mechanisms by which brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB transform the brain from normal to epileptic, a process termed epileptogenesis; and to develop peptide and small molecule inhibitors of TrkB signaling for prevention and disease modification of temporal lobe epilepsy.


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.


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