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
Harward, Stephen C., et al. “Autocrine BDNF-TrkB signalling within a single dendritic spine.” Nature, vol. 538, no. 7623, Oct. 2016, pp. 99–103. Pubmed, doi:10.1038/nature19766. Full Text
Hedrick, Nathan G., et al. “Rho GTPase complementation underlies BDNF-dependent homo- and heterosynaptic plasticity.” Nature, vol. 538, no. 7623, Oct. 2016, pp. 104–08. Pubmed, doi:10.1038/nature19784. Full Text
Gu, Bin, et al. “A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cγ1 Prevents Epilepsy Induced by Status Epilepticus.” Neuron, vol. 88, no. 3, Nov. 2015, pp. 484–91. Pubmed, doi:10.1016/j.neuron.2015.09.032. Full Text Open Access Copy
Puranam, Ram S., et al. “Disruption of Fgf13 causes synaptic excitatory-inhibitory imbalance and genetic epilepsy and febrile seizures plus.” J Neurosci, vol. 35, no. 23, June 2015, pp. 8866–81. Pubmed, doi:10.1523/JNEUROSCI.3470-14.2015. Full Text
Helgager, Jeffrey, et al. “Brain-derived neurotrophic factor but not vesicular zinc promotes TrkB activation within mossy fibers of mouse hippocampus in vivo.” J Comp Neurol, vol. 522, no. 17, Dec. 2014, pp. 3885–99. Pubmed, doi:10.1002/cne.23647. Full Text
He, Xiao Ping, et al. “Impairment of kindling development in phospholipase Cγ1 heterozygous mice.” Epilepsia, vol. 55, no. 3, Mar. 2014, pp. 456–63. Pubmed, doi:10.1111/epi.12536. Full Text
Harward, S. C., and J. O. McNamara. “Aligning animal models with clinical epilepsy: Where to begin?” Advances in Experimental Medicine and Biology, vol. 813, Jan. 2014, pp. 243–51. Scopus, doi:10.1007/978-94-017-8914-1-19. Full Text
Harward, S. C., and J. O. McNamara. “Aligning animal models with clinical epilepsy: Where to begin?” Advances in Experimental Medicine and Biology, vol. 813, Jan. 2014, pp. 243–51. Scopus, doi:10.1007/978-94-17-8914-1_19. Full Text
Harward, Stephen C., and James O. McNamara. “Aligning animal models with clinical epilepsy: where to begin?” Adv Exp Med Biol, vol. 813, 2014, pp. 243–51. Pubmed, doi:10.1007/978-94-017-8914-1_19. Full Text