Norepinephrine is one of six amines in the central nervous system which project widely to cerebral cortex from nuclei in the basal forebrain and brainstem. Norepinephrine appears to play a significant role in the pathophysiology of epilepsy, yet little is known about its function or even which cells are the target cells for its action. Using rat cerebral cortex in dissociated culture, a multidisciplinary approach to understanding the functions of norepinephrine in cerebral cortex will be undertaken. Preliminary electrophysical studies have shown that the predominant effect of norepinephrine in these cultures is to increase the synaptic activity without a significant direct effect on the impaled cell. There is evidence that this effect is being mediated by a subpopulation of responsive neurons which are small (9-10 microns) and, therefore, not routinely impaled. The physiology of these cells will be pursued by patch clamp recording techniques which will allow recording from this relatively inaccessible neuronal type. The possibility of an effect on synaptic transmission will be investigated by using 2 cell recording from monosynaptically coupled neurons. In addition, the pharmacology of this response will be carefully defined. Other possible functions of norepinephrine will be considered, specifically, a role in regulation of cerebral glycogen metabolism. The effect of norepinephrine on glycogen turnover in neocortex in dissociated culture will be investigated, including the pharmacology, localization, and underlying mechanism of the response. Special attention will be paid to the possibility of interactions between glia and neurons linking neuronal activity with glial metabolism. Finally, localization of adrenergic receptors in the culture will be attempted using radioligand autoradiography and immunocytochemistry. This research will hopefully elucidate the functions, mechanisms of action, and cellular organization of the noradrenergic projection to cerebral cortex, and will provide a basis for pursuing similar questions regarding other important cerebral amines.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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Neurological Disorders Program Project Review B Committee (NSPB)
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Children's Hospital Boston
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