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Steve Rothman, M.D. Professor, Department of Pediatric Neurology E-mail: srothman@umn.edu

Research Interests:

My colleagues and I have broad interests in the fundamental neurobiology of epilepsy and utilizing this knowledge to improvise new therapies for intractable epilepsy. We are especially interested in adapting new devices developed by the engineering community for eventual clinical use. There are three laboratory projects related to this fundamental objective.

1. Recent experiments have investigated a potential new modality of epilepsy therapy, rapid cooling utilizing small thermoelectric (Peltier) devices. We have shown that we can rapidly terminate acute neocortical seizures in vitro and in vivo if we activate a Peltier device in contact with the seizure focus. We have developed an automated, closed loop seizure recognition system that can successfully activate the cooling device. In order to accomplish this work, we have developed very robust and reliable models of experimental epilepsy, based upon inhibition of neuronal potassium channels. We are in the process of extending our initial work on rodent seizures to more relevant clinical models.

2. A second set of experiments is investigating the hypothesis that activation of tonic, high affinity, extrasynaptic GABA A receptors in cortex or hippocampus may be able to terminate focal seizures. We have completed initial experiments using cultured neurons, a new caged GABA analog, and a small, ultraviolet light emitting diode (LED) to demonstrate that GABA uncaging is capable of rapidly suppressing paroxysmal discharges . We plan to extend these observations to brain slice and then intact cortex.

3. Other in vitro work has recently explored the mechanism of action of the antiepileptic drug levetiracetam. While the drug has little, if any effect on monosynaptic transmission, it does suppress bursts of repetitive synaptic potentials, most likely by interfering with the release of neurotransmitter. New physiological and optical imaging experiments in tissue culture will more accurately identify the mechanism of this effect and define its time course.

We continue to collaborate with colleagues at other institutions on seizure-induced spine changes in cortical neurons and the possibility of utilizing leptin as an antiepileptic drug.

Selected Publications:

Thio, LL, Yang, X-F, Rothman, SM, Weisenfeld, AE, and Yamada, KA. Leptin inhibits 4-Aminopyridine and Pentylenetetrazole induced seizures and AMPAR mediated synaptic transmission. Journal of Clinical investigation, 2008, 118:272-280.

Zeng, LH, Xu L, Rensing, NR, Sinatra, PM, Rothman, SM, and Wong,M. Kainate seizures cause acute dendritic injury and actin depolymerization in vitro . Journal of Neuroscience, 2007, 27:11604-11613

Yang, X-F, Weisenfeld, A, and Rothman, SM. Prolonged exposure to levetiracetam: reveals a presynaptic effect on neurotransmission. Epilepsia, 2007, 48:1861 - 1869.

Rothman, SM, Perry, G, Yang, X-F, Hyrc , K, and Schmidt, BF. Optical suppression of seizure-like activity with an LED. Epilepsy Research, 2007, 74:201-209.

Yang, X-F, Kennedy, BR, Lomber, SG, Schmidt, RE, and Rothman, SM. Cooling produces minimal neuropathology in neocortex and hippocampus. Neurobiology of Disease, 2006,23:637-643.

Hilderbrand, JK, Peterson, GP, and Rothman, SM. Development of a phase change heat spreader to enable focal cooling as a treatment for intractable neocortical epilepsy. Heat Transfer Engineering, 2007, 28:282-291 .

Rensing, N, Ouyang, Y, Yang, X-F, Yamada, KA, Rothman, SM, Wong, M. In vivo imaging of dendritic spines during electrographic seizures. Annals of Neurology, 2005, 58:888-898.

Burton , J, Peebles , GA , Binder, DK, Rothman, SM, Smyth , MD. Transcortical cooling inhibits hippocampal-kindled seizures in the rat. Epilepsia, 2005, 46: 1881-1887.

Yang, X-F, Ouyang, Y, Kennedy, BR, and Rothman, SM. Cooling blocks rat hippocampal neurotransmission by a presynaptic mechanism: Observations using 2- photon microscopy. Journal of Physiology ( London ), 2005, 567: 215-224.