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Adrenergic receptor mediated suppression of seizures: [[alpha].sub.2] adrenergic receptors inhibit epileptiform activity via a synapse specific mechanism.

Introduction. The brain adrenergic system is a diverse projection of norepinephrine releasing neurons which regulate many cognitive functions including attention and arousal. Several lines of evidence have shown an important role for this system in the control of epilepsy. Recent studies have shown that correct manipulation of the adrenergic system may not only be effective against currently intractable epilepsies, but more importantly, may abolish seizures without deleterious side effects on learning and memory, as is experienced with many current antiepileptic therapies. This makes exploitation of adrenergic mechanisms a prime target for new antiepileptic treatments. However, because of the complexity of the adrenergic signaling system, research into the exact mechanism of the adrenergic system's effects on seizures had been hindered. Fortunately, new advances in technology and selective pharmacological agents have made it possible to begin to define the mechanisms involved in the adrenergic system's antiepileptic capabilities.

Integral in learning and memory processes, hippocampal CA3 pyramidal cells and are a common focus in temporal lobe epilepsy. Our lab has identified an [[alpha].sub.2A] adrenergic receptor (AR) mediated response on hippocampal CA3 pyramidal neurons which robustly inhibits epileptiform activity. Present studies have localized this response to the CA3 pyramidal cells themselves, showing no reduction of effect in the presence of pharmacological and surgical isolation. We have examined neurotransmission evoked from the major connections of the CA3 pyramidal neurons to further localize this particular adrenergic effect.

Methods. Using whole-cell recordings in rat hippocampal slices, we examined the effect of [[alpha].sub.2] AR stimulation on excitatory post-synaptic currents (EPSCs) evoked from the major CA3 synaptic inputs (mossy fiber and CA3-CA3 recurrent), as well as from the CA3 inputs onto CA1 pyramidal neurons.

Results. EPSCs evoked from the mossy fiber-CA3 pathway and the CA3-CA1 pathway showed no reduction in response to [alpha]AR stimulation with epinephrine in the presence of 10[micro]M timolol. In contrast, EPSCs evoked from the CA3-CA3 recurrent synapses were inhibited under the same conditions.

Conclusions. Preliminary evidence suggests that only CA3-CA3 recurrent synaptic strength is inhibited by [[alpha].sub.2]AR stimulation, while the excitatory drive to and from the CA3 cells is not inhibited. Overexcitation of the CA3 recurrent synapses is thought to be essential in temporal lobe seizures. Since this [[alpha].sub.2]AR response is specific to the CA3 recurrent synapses, this may explain how the adrenergic system is antiepileptic while at the same time not affecting other areas of cognitive function such as learning or memory.

Acknowledgments: Supported by NIH HL61438 (DMP), ND EPSCoR through NSF grant EPS-0447679 (VAD), NSF CAREER award 0347259 (VAD), and NIH COBRE program grant 5P20RR017699 (VAD).

Chris WD Jurgens * and Van A Doze

Department of Pharmacology, Physiology & Therapeutics, School of Medicine & Health Sciences University of North Dakota, Grand Forks, ND, 5 8203
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Author:Jurgens, Chris W.D.; Doze, Van A.
Publication:Proceedings of the North Dakota Academy of Science
Date:Apr 1, 2007
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