The studies carried out in the previous 5 year period were designed to examine features of the biochemical and connectional maturation of the rhesus monkey cerebral cortex during the prenatal and early postnatal periods of development. An important finding from our studies of emerging transmitter systems has been the recognition of a class of early appearing transmitter and receptor systems which are present within the ventricular proliferative zones in advance of the period of synaptogenesis and during the major wave of cell proliferation and differentiation. GABA is one of these early expressed transmitter systems, and based upon the cellular distribution of its receptors and the large number of cells and processes containing GABA within the proliferative zones, we have hypothesized that it may play an important role in the regulation of developmental processes such as cell proliferation and differentiation. We propose to test this hypothesis using primary cultures to examine the role of GABA, GABA receptor agonists and antagonists and antisense oligonucleotides to GAD and GABAA receptor subunits in the regulation of cell number, commitment to transmitter related cellular phenotypes and cell survival. Video imaging methods will also be applied to slice preparations and dissociated cultures to examine the role of changes in intracellular Ca++ levels resulting from these treatments in the regulation of these processes. The findings of these in vitro studies will be followed-up using an in vivo model of cortical development and differentiation. Microinjections of selected compounds will be made into the cerebral ventricles of fetal rats and monkeys to confirm the findings of the in vitro analyses and to assess the impact of these agents on the cytoarchitectonic organization and areal phenotypes of the intact cerebral cortex. Finally, we will continue our studies of the mechanisms involved in the development of areal connectivity directly within the primate cerebral cortex. Specific questions these studies will address are: 1) do corticocortical axons enter the cortical plate in a diffuse or restricted manner; and 2) is the pattern of interdigitating and distinctive territories characteristic of select populations of corticocortical terminations set up prior to, or after the growth of axons into the cortical plate? These studies will utilize injections of HRP and 3H-leucine and proline in combination with quantitative analysis of the distributions of labeled axons to address these questions at selected fetal ages. The data from these experiments, combined with the results of other projects in this program are expected to advance our understanding of the mechanisms which specify essential features characteristic of the different areal phenotypes within the cerebral cortex.

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Yale University
New Haven
United States
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