This application describes experiments designed to explore the biology if the somatostatin (SS) containing interneurons of the mammalian cerebral cortex. Studies will include experiments examining the appearance and development if this cell in vivo and in vitro. Hormonal and metabolic alterations will be induced in order to determine the necessary elements for the normal ontogenesis of this peptidergic neuron. In addition, our in vitro model allows us to explore the selective involution of the SS neuron. The roles of hormones and neurotransmitters which regulate SS cells in this senescence will be explored. Secondly, the influences of the major endogenous cortical neurotransmitters on SS secretion will be examined separately and in concert. These studies will focus on acetylcholine (Ach), glutamate, and GABA. Selective enzyme inhibitors, receptor antagonists, and agonists for each will be tested to provide insights into potential phystological influences. The third major focus attempts to discover a physiologic role for SS on cortical cells. The effects of SS peptides in the turnover of GABA, glutamate and ACh will be tested in isolated brain fragments and to cultured rat cerebral cortical cells. The SS effects will be compared to that of other cortical peptides (VIP, CCK, and CRF). Finally, through a collaboration with the section of Neurosurgery, freshly removed fragments of human cerebral cortex will be made available to study SS secretion and action. We will examine interactions between the transmitters glutamate, acetylcholine and GABA and somatostatic. Cortex fragments from patients with a variety of neurologic disorders will be studied. These studies impact directly on common human neurologic disease states in which SS has been shown to be selectively depleted in the neocortex (Aizheimer's disease, and the dementia of Parkinson's disease) and in the hippocampus (epilepsy). The studies are designed to provide insights into the pathogenesis of these major health problems and into the normal chemical reactions underlying complex memory and learning behaviors.
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