James O'Connell McNamara
Duke School of Medicine 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
Huang, Yang Z., and James O. McNamara. “Mutual regulation of Src family kinases and the neurotrophin receptor TrkB.” J Biol Chem, vol. 285, no. 11, Mar. 2010, pp. 8207–17. Pubmed, doi:10.1074/jbc.M109.091041. Full Text
Danzer, Steve C., et al. “Structural plasticity of dentate granule cell mossy fibers during the development of limbic epilepsy.” Hippocampus, vol. 20, no. 1, Jan. 2010, pp. 113–24. Pubmed, doi:10.1002/hipo.20589. Full Text
Dassie, Justin P., et al. “Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors.” Nat Biotechnol, vol. 27, no. 9, Sept. 2009, pp. 839–49. Pubmed, doi:10.1038/nbt.1560. Full Text
Alexander, Georgia M., et al. “Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors.” Neuron, vol. 63, no. 1, July 2009, pp. 27–39. Pubmed, doi:10.1016/j.neuron.2009.06.014. Full Text
Ma, H., et al. “Synthesis of magnetic porous hollow silica nanotubes for drug delivery.” Journal of Applied Physics, vol. 105, no. 7, Apr. 2009. Scopus, doi:10.1063/1.3072048. Full Text
McNamara, J. O., et al. Plasticity of dentate granule cell mossy fiber synapses: A Putative mechanism of limbic epileptogenesis. Dec. 2008, pp. 715–29. Scopus, doi:10.1007/978-0-387-77232-5_24. Full Text
Tahirovic, Yesim A., et al. “Enantiomeric propanolamines as selective N-methyl-D-aspartate 2B receptor antagonists.” J Med Chem, vol. 51, no. 18, Sept. 2008, pp. 5506–21. Pubmed, doi:10.1021/jm8002153. Full Text
Roeloffs, Rosemarie, et al. “In vivo profile of ICA-27243 [N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide], a potent and selective KCNQ2/Q3 (Kv7.2/Kv7.3) activator in rodent anticonvulsant models.” J Pharmacol Exp Ther, vol. 326, no. 3, Sept. 2008, pp. 818–28. Pubmed, doi:10.1124/jpet.108.137794. Full Text
Huang, Yang Z., et al. “Zinc-mediated transactivation of TrkB potentiates the hippocampal mossy fiber-CA3 pyramid synapse.” Neuron, vol. 57, no. 4, Feb. 2008, pp. 546–58. Pubmed, doi:10.1016/j.neuron.2007.11.026. Full Text