J. Victor Nadler

Research in this laboratory focuses primarily on mechanisms of epileptogenesis, that is, the process by which normal brain tissue becomes prone to seizures. Additional studies concern the mechanisms of excitatory synaptic transmission in the mammalian brain. 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, neurons generated as a result of seizures migrate to aberrant locations, become incorporated into the reverberating excitatory circuit and fire spontaneously. We are studying the physiology and pharmacology of this circuit and its role in epileptogenesis with use of brain tissue from animals that have been made epileptic. Properties of recurrent mossy fiber synapses and ectopically-located hyperexcitable neurons 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. Aspartate is co-released with glutamate from some excitatory terminals in the brain. Recent data indicate that aspartate and glutamate are released by distinct mechanisms. However, the role of aspartate in excitatory transmission is currently unknown. One possibility suggested by our findings is that aspartate serves a paracrine function, targeting extrasynaptic NMDA receptors. Extrasynaptic and synaptic NMDA receptors couple to different signaling mechanisms and have opposite effects on cell survival. Thus the aspartate release/extrasynaptic NMDA receptor pathway offers a new target for pharmacological intervention in neuropsychiatric disease.