MOLECULAR ANALYSIS OF NEURONAL PHENOTYPE IN HIPPOCAMPUS

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The goal is to identify and characterize biochemical parameters that distinguish neuronal cell types within the hippocampal formation. The hippocampus is chosen as a model for cellular and regional specific gene expression because of its relatively simple anatomical organization, consisting of only several major neuronal cell types and because of its well characterized developmental, electrophysiological and neurotransmitter properties. We will examine the anatomical distribution of the expression of specific mRNA transcripts both within the defined subnuclear organization of the hippocampus and with respect to their potential expression in neurons of other regions of the brain. The developmental program of expression will be investigated in both normal and mutant strains of mice to distinguish those transcripts accumulated during cell migration from those expressed only after synaptogenesis. The primary sequence of the encoded protein will be determined and evaluated in terms of potential signal peptides, glycosylation and proteolytic cleavage. These post-translational modifications, together with the neuroanatomical distribution of their expression, should provide important clues as to the nature of the specific proteins. It is believed that these studies will contribute to an understanding of the biochemical basis of hippocampal function. Experimentally induced lesion and clinical studies have associated the hippocampal formation with such complex behavioral phenomena as acquisition and processing of short term memory and propagation of epileptic seizures. For example, a potential animal model for certain forms of epilepsy in humans, the mutant mouse strain "tottering", will be examined for alterations in patterns of gene expression which may result from the primary defect of hyperinnervation by noradrenergic axons of the locus coeruleus to the hippocampal formation. These studies, therefore, could result in future examination of the role of specific gene products during experimentally induced seizure activity.