James O. McNamara, MD, PI
The goal of this laboratory 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 inhibited TLE (Gu et al., 2015). This provides proof-of-concept evidence for a novel strategy targeting receptor tyrosine kinase signaling and identifies a therapeutic with promise for prevention of TLE caused by status epilepticus in humans.
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).
- 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. PMC4636438
- 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. Nature 538(7623):99-103, 2016.
- He X.P., Minichiello L., Klein R. and McNamara J.O. Immunohistochemical evidence of seizure-induced acti-vation of trkB receptors in the mossy fiber pathway of adult mouse hippocampus. J. Neurosci., 22:7502-7508, 2002.
- He, X., Kotloski, R., Nef, S., Luikart, B.W., Parada, L.F., and McNamara, J.O. Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model. Neuron 43:31-42, 2004.
- 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 538(7623):99-103, 2016.
- Huang Y, He X, Krishnamurthy K, and McNamara J. O. (2019). TrkB-Shc Signaling protects against hippocampal injury following status epilepticus. J Neurosci 39(23):4624-4630, 2019.
- 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).
- Huang, Y.Z., Pan, E., Xiong, Z.Q., and McNamara, J.O. Zinc-mediated transactivation of TrkB potentiates the hippocampal mossy fiber CA3 pyramid synapse. Neuron, 57:546-558, 2008.
- Pan, E., Zhang, Xiao-an, Huang, Z., Krezel, A., Zhao, M., Tinberg, C.E., Lippard, S.J., and McNamara, J.O. , Vesicular Zinc Promotes Presynaptic and Inhibits Postsynaptic Long-Term Potentiation of Mossy Fi-ber-CA3 Synapse. Neuron 71:1116-1126, 2011. (PMCID: PMC3184234)