Development of the cerebral cortex is critically dependent on synaptic activity. Recognition of this fact dates to the pioneering work of Drs. Hubel and Wiesel who demonstrated the final pattern of synaptic connectivity is determined by use of the neural system during a postnatal epoch referred to as the critical period. More recent studies have demonstrated that the essential synaptic signal involves activation of N-methyl-D-aspartate (NMDA)-type glutamate receptors on postsynaptic neurons resulting in synaptic enhancement that follows Hebbian principles of learning and memory. An important corollary of these observations is that normal cortical development is altered by conditions that disturb natural patterns of synaptic interaction. In an effort to determine how receptor activation effects long-term changes in properties of neurons in the developing cortex, the investigators and others have demonstrated that synaptic activity regulates the expression of cellular IEGs that encode transcription factors. These observations suggest that coordinated programs of gene activation may underlie neuronal responses to activity. With the broad objective of testing this hypothesis, the investigators have used molecular cloning techniques to identify genes that are rapidly regulated by activity in neurons of the developing cortex. In addition to the anticipated transcription factors, they have identified a small subset of these genes that appear to encode molecules that can directly modify neuronal properties. An example of such an """"""""effector"""""""" molecule is the novel, inducible form of prostaglandin synthase (Yamagata et al., 1993). The focus of this proposal is to examine the function of three novel effector molecules that are rapidly regulated by activity in the developing cortex. ARC is a 55kD protein that contains 150 aa domain that is homologous to spectrin and is enriched in dendrites. Biochemical and immunohistochemical studies indicate that ARC interacts with the neuronal cytoskeleton. ARC is strongly induced in association with physiological plasticity and it is hypothesized that ARC may function to link activity with changes in dendrite morphology. Experiments in Aim 1 will identify proteins that interact with ARC and examine their role in dendrite growth and morphology. NARP is a novel member of the pentraxin family of secreted calcium and phospholipid dependent lectins. Binding sites for plant lectins (concanavilin A or pea lectin) are enriched in the developing cortex, but few natural ligands are known. NARP messenger ribonucleic acid (mRNA) is developmentally regulated and strongly induced in neurons by physiological activity. Experiments in Aim 2 will test the hypothesis that NARP is a lectin that can modify properties of the extracellular matrix in response to activity and thereby influence cell growth or other cellular properties. RHEB is a novel member of the Ras family of small guanosine triphosphate (GTP) binding proteins that is homologous to H-Ras and is unique among Ras family members in being regulated as an IEG in brain neurons. Like H-Ras, RHEB is capable of transforming cultured fibroblasts indicating that RHEB can influence cell growth. Ras proteins function as molecular switches to regulate the activity of specific cellular pathways. Because RHEB is rapidly regulated by transmitters and growth factors, it is hypothesized that the putative RHEB pathway plays a role in neuronal responses to these signals. Experiments in Aim 3 will identify proteins involved in the RHEB pathway and examine their effect on cell growth and differentiation.
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