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Professor of Pharmacology and Cancer Biology
Professor of Neurobiology
Duke University School of Medicine
Durham, NC 27710
Research in this laboratory focuses primarily on mechanisms of epileptogenesis, that is, the process by which normal brain tissue becomes prone to seizures. We use an interdisciplinary approach that involves diverse methodologies, including cellular electrophysiology, immunocytochemistry, electron microscopy, confocal microscopy and high speed imaging.
• In persons with temporal lobe epilepsy, the most common form of epilepsy in adults, mossy fibers in the hippocampus form a reverberating excitatory circuit that probably contributes to seizure development. In addition, inhibitory neurons die and newly-born spontaneously-firing neurons become integrated into the network. We are studying the physiology and pharmacology of this abnormal circuitry with use of brain tissue from animals that have been made epileptic. Its unique properties may be exploited to develop novel approaches toward the treatment of temporal lobe epilepsy.
• In addition, we are investigating the mechanism and significance of aspartate release from synaptic terminals. Aspartate is co-released with glutamate or GABA from some synaptic terminals in the brain. Recent data indicate that aspartate is released by a mechanism distinct from that of glutamate and GABA. The unique pharmacology of aspartate release is being exploited to determine its role in brain function. Aspartate co-release may offer a new target for pharmacological manipulation of brain mechanisms relevant to neuropsychiatric disease.
Feng, L., Molnár, P. and Nadler, J.V., Short-term frequency-dependent plasticity at recurrent mossy fiber synapses of the epileptic brain, J. Neurosci., 23, 5381-5390 (2003).
Bradford, S.E. and Nadler, J.V., Aspartate release from rat hippocampal synaptosomes, Neuroscience, 128, 751-765 (2004).
Tu, B, Timofeeva, O, Jiao, Y and Nadler, J.V., Spontaneous release of neuropeptide γ tonically inhibits recurrent mossy fiber synaptic transmission in epileptic brain, J. Neurosci., 25, 1718-1729 (2005).
Jiao, Y. and Nadler, J.V., Stereological analysis of GluR2-immunoreactive hilar neurons in the pilocarpine model of temporal lobe epilepsy: correlation of cell loss with mossy fiber sprouting, Exp. Neurol., 205, 569-582 (2007).
Nadler, J.V., Axon sprouting in epilepsy, in Encyclopedia of Epilepsy Research, Vol. 3 (Schwartzkroin, PA, ed.). Academic, Oxford, pp. 1143-1148 (2009).
Zhan, R.-Z. and Nadler, J.V., Enhanced tonic GABA current in normotopic and hilar ectopic dentate granule cells after pilocarpine-induced status epilepticus, J. Neurophysiol., 102, 670-681 (2009).
Zhang, X. and Nadler, J.V., Postsynaptic response to stimulation of the Schaffer collaterals with properties similar to those of synaptosomal aspartate release, Brain Res., 1295, 13-20 (2009).
Zhan, R.-Z., Timofeeva, O., and Nadler, J.V., High ratio of synaptic excitation to synaptic inhibition in hilar ectopic granule cells of pilocarpine-treated rats, J. Neurophysiol., 104, 3293-3304 (2010).
Nadler, J.V., Aspartate release and signalling in the hippocampus, Neurochem Res., 36, 668-676 (2011).
Cameron, M.C., Zhan, R.-Z., and Nadler, J.V., Morphologic intergration of hilar ectopic granule cells into dentate gyrus circuitry in the pilocarpine model of temporal lobe epilepsy, J. Comp. Neurol., 519, 2175-2192 (2011).