This project is designed to test hypotheses concerning the role of the neuromodulators, acetylcholine, norepinephrine, and dopamine in the epileptic brain. Two kinds of electrophysiological experiments will be performed: the first, to assess the effects of the neuromodulators on the excitability of neocortical neurons; the second to determine how each of these neuromodulators interacts with amino acid neurotransmitters in these neurons. Experiments will be conducted on brain slices taken from neocortical tissue that has been surgically removed in the course of treatment for catastrophic childhood epilepsy. The brain samples to be studied will come from the clinically defined Zone of Cortical Abnormality (ZCA) (Project 1). Experiments will be carried out on samples of the ZCA considered to be """"""""least"""""""" and """"""""most"""""""" abnormal. Because neocortical tissue will be taken from patients ranging in age from a few months to the early teens, it will also be possible to test hypotheses concerning the developmental role of the neuromodulators. After the electrophysiological experiments have been completed, neurons will be marked intracellularly with biocytin to identify the location and morphology of the recorded cells, and to permit further histological analysis. This study of the interactions between amino acid neurotransmitters and neuromodulators will provide an in vitro model more closely resembling the in vivo situation than studies of either modulators or neurotransmitters alone. It is anticipated that the results of these experiments will be important for understanding both the epileptogenic process and key aspects of neuronal development.
