Professor of Neurobiology
Professor of Neurology
Professor of Pharmacology and Cancer Biology
Director, Center for Translational Neuroscience
Faculty Network Member of the Duke Institute for Brain Sciences
401C Bryan Research Building
Box 3209, DUMC
Dept: Neurobiology
Email: jmc@neuro.duke.edu
Phone: 919-684-0323
McNamara Lab
Overview
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 terminals of the mossy fiber axons of the dentate granule cells. Giant boutons of these terminals form excitatory synapses with specialized spines of CA3 pyramidal cells. Filopodial extensions of these boutons form synapses on interneurons which in turn provide feedforward disynaptic inhibition of the CA3 pyramidal cells. We utilize a diversity of electrophysiological, imaging, and molecular tools in in vivo, ex vivo, and in vitro studies to understand how BDNF/TrkB dependent plasticities within this microcircuit promote epileptogenesis.
Featured Publications
- 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)
McNamara Publications
Pan, Enhui, Ram S. Puranam, and James O. McNamara. “Long-Term Potentiation of Mossy Fiber Feedforward Inhibition of CA3 Pyramidal Cells Maintains E/I Balance in Epilepsy Model.” Eneuro 9, no. 1 (January 2022). https://doi.org/10.1523/ENEURO.0375-21.2021.
Drysdale, Nicolas D., Elizabeth Matthews, Elizabeth Schuetz, Enhui Pan, and James O. McNamara. “Intravenous kainic acid induces status epilepticus and late onset seizures in mice.” Epilepsy Res 178 (December 2021): 106816. https://doi.org/10.1016/j.eplepsyres.2021.106816.
French, Jacqueline A., Martina Bebin, Marc A. Dichter, Jerome Engel, Adam L. Hartman, Sergiusz Jóźwiak, Pavel Klein, James McNamara, Roy Twyman, and Paul Vespa. “Antiepileptogenesis and disease modification: Clinical and regulatory issues.” Epilepsia Open 6, no. 3 (September 2021): 483–92. https://doi.org/10.1002/epi4.12526.
López-Álvarez, Marina, Marjolein Heuker, Jorrit W. A. Schoenmakers, Gooitzen M. van Dam, James O. McNamara, Jan Maarten van Dijl, and Marleen van Oosten. “The smart activatable P2&3TT probe allows accurate, fast, and highly sensitive detection of Staphylococcus aureus in clinical blood culture samples.” Sci Rep 10, no. 1 (November 5, 2020): 19216. https://doi.org/10.1038/s41598-020-76254-4.
Lin, Thiri W., Stephen C. Harward, Yang Zhong Huang, and James O. McNamara. “Targeting BDNF/TrkB pathways for preventing or suppressing epilepsy.” Neuropharmacology 167 (May 1, 2020): 107734. https://doi.org/10.1016/j.neuropharm.2019.107734.
Krishnamurthy, Kamesh, Yang Zhong Huang, Stephen C. Harward, Keshov K. Sharma, Dylan L. Tamayo, and James O. McNamara. “Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure.” Ann Neurol 86, no. 6 (December 2019): 939–50. https://doi.org/10.1002/ana.25602.
Anderson, Robert J., James J. Cook, Natalie Delpratt, John C. Nouls, Bin Gu, James O. McNamara, Brian B. Avants, G Allan Johnson, and Alexandra Badea. “Small Animal Multivariate Brain Analysis (SAMBA) - a High Throughput Pipeline with a Validation Framework.” Neuroinformatics 17, no. 3 (July 2019): 451–72. https://doi.org/10.1007/s12021-018-9410-0.
Huang, Yang Zhong, Xiao-Ping He, Kamesh Krishnamurthy, and James O. McNamara. “TrkB-Shc Signaling Protects against Hippocampal Injury Following Status Epilepticus.” J Neurosci 39, no. 23 (June 5, 2019): 4624–30. https://doi.org/10.1523/JNEUROSCI.2939-18.2019.
Pan, Enhui, Zirun Zhao, and James O. McNamara. “LTD at mossy fiber synapses onto stratum lucidum interneurons requires TrkB and retrograde endocannabinoid signaling.” J Neurophysiol 121, no. 2 (February 1, 2019): 609–19. https://doi.org/10.1152/jn.00669.2018.
Dingledine, Raymond, Douglas A. Coulter, Brita Fritsch, Jan A. Gorter, Nadia Lelutiu, James McNamara, J Victor Nadler, et al. “Transcriptional profile of hippocampal dentate granule cells in four rat epilepsy models.” Sci Data 4 (May 9, 2017): 170061. https://doi.org/10.1038/sdata.2017.61.