The goal of the proposed research is to understand the developmental relationships of neurons that use either acetylcholine (ACh) or gamma-aminobutyric acid (GABA) as their synaptic transmitter. The first specific aim is to compare the generation of ACh and GABA neurons by combining 3H-thymidine radioautography and immunocytochemistry of the ACh or GABA synthesizing enzymes choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD), respectively. These studies will be conducted in brain regions that allow developmentally interesting comparisons, such as ones where GABA cells are projection neurons and ACh cells are interneurons. Regions where ACh or GABA neurons have been implicated in Alzheimer's disease, Down's syndrome, epilepsy, and Huntington's disease will also be studied to determine whether unusual generation patterns of ACh and GABA neurons are peculiar to regions susceptible to these neurological disorders. The second specific aim is to determine when ChAT and GAD are developmentally expressed relative to the birthdates of ACh and GABA neurons. These studies will rely on immunocytochemical and biochemical methods, and will be focused on whether or not the neurotransmitter synthesizing enzymes can be demonstrated within neuronal precursor cells prior to their final DNA synthesis or migration to their final locations in adult CNS. The third specific aim is to determine whether differences in the birthdates of ACh and GABA neurons may be associated with topographical differences in the innervation patterns between the two populations. Initial studies will concentrate upon demonstrating such differences for GABA synaptic terminals upon functionally different domains (e.g., distal dendrites vs. somata) of ACh neurons in double immunocytochemically labeled preparations. The fourth specific aim is to conduct collaborative studies with other projects proposed in this application. Examples of such investigations include a) studies of polypeptide expression in developing neurons; b) colocalization of ChAT and molecules specific for subclasses of developing and adult ACh neurons; and c) correlative studies of the development of neurotransmitter phenotype and the maturation of neurosecretory activity. It is anticipated that the results of the various studies proposed in this project will provide information fundamental to understanding the development of cholinergic and GABAergic functions in normal brain and in certain neurological disorders.
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