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.

Molnár, P. and Nadler, J.V., Lack of effect of mossy fiber-released zinc on granule cell GABAA receptors in the pilocarpine model of epilepsy, J. Neurophysiol., 85, 1932-1940 (2001).

Molnár, P. and Nadler, J.V., Synaptically-released zinc inhibits NMDA receptor activation at recurrent mossy fiber synapses, Brain Res., 910, 205-207 (2001).
Okazaki, M.M. and Nadler, J.V., Glutamate receptor involvement in dentate granule cell epileptiform activity evoked by mossy fiber stimulation, Brain Res., 915, 58-69 (2001).

Dashtipour, K., Tran, P.H., Yan, X.-X., Okazaki, M.M., Nadler, J.V. and Ribak, C.E., Quantitative and morphological analysis of dentate granule cells with recurrent basal dendrites from normal and epileptic rats, Hippocampus, 12, 235-244 (2002).

Nadler, J.V., The recurrent mossy fiber pathway of the epileptic brain, Neurochem. Res., 28, 1649-1658 (2003).

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 Y tonically inhibits recurrent mossy fiber synaptic transmission in epileptic brain, J. Neurosci., 25, 1718-1729 (2005).

Zhan, R.-Z., Nadler, J.V. and Schwartz-Bloom, R.D., Depressed responses to applied and synaptically-released GABA in CA1 pyramidal cells, but not in CA1 interneurons, after transient forebrain ischemia, J. Cereb. Blood Flow Metab., 26, 112-124 (2006).

Timofeeva, O. and Nadler, J.V., Facilitation of granule cell epileptiform activity by mossy fiber-released zinc in the pilocarpine model of temporal lobe epilepsy, Brain Res., 1078, 227-234 (2006).