Research proposal: Cortical development depends on a sequence of cellular interactions involving growth factors and neurotransmitters. In adult brain, these molecules induce the rapid and transient expression of proteins that may control long-term responses. Analogous novel regulatory genes, induced by synaptic activity and expressed at high levels, at critical periods, in developing cortex were identified in Dr. Worley's laboratory by molecular cloning techniques. Adr-1 encodes a 45 kD protein with homology to spectrin, that appears to be brain specific and expressed during the critical postnatal period, suggesting a link between extracellular stimuli and changes in neuronal morphology. Rasp encodes a GTP-binding protein with homology to ras (40% identity) and rap (45% identity) and is expressed in the prenatal rat cortex. Like ras, rasp transforms NIH3T3 cells, indicating an active role in cellular signalling. The central hypothesis is that physiological activity induces the expression of both adr-1 and rasp and also modulates their intracellular localization. This will be tested, in normal rat cortex, in Aims 1 and 2, respectively. After obtaining this basic framework, a similar study will be performed in two animal models, characterized by decreased cortical input, and relevant for mental retardation: rats with nutritional-environmental deprivation and mice with basal forebrain neonatal lesions (Aims 3 and 4). Environment: Dr. Kaufmann's activities will be in the context of the Mental Retardation Center, which comprises several research groups studying different aspects of development relevant to mental retardation such as gene expression in brain development.
