The central purpose of this research is the study of cellular interactions during fetal central nervous system (CNS) development which may result in birth defects and mental retardation. Another objective is to study transplantation of immature neocortical neurons as a possible future therapy for childhood diseases with neuronal loss. Selective photothermolysis and photolysis by singlet oxygen (102) are novel mechanisms by which brief, unfocused laser pulses cause selective damage to entire subpopulations of cells containing chromophores with absorption in the nearinfrared range. A newly developed latex nanosphere delivery system can deliver sufficient dye to targeted subpopulations of cells to allow selective damage in vivo. Abnormalities of structure, organization, and function will be studied within Specific Aims I to III using innovative methods to cause nonivasive, selective, cell-specific damage to subpopulations of cells within the mammalian CNS (see Significance). Developmental studies using lesions to specific populations of cells at defined times and in defined areas during embryogenesis will more precisely determine the temporal impact of specific cellular elements on later CNS structure. Studies of migration and ultrastructural integration of immature neocortical neurons after transplantation into lesioned areas will begin to assess the feasibility of this possible future therapy for neocortical injury (Specific Aim IV). In the future, grafted cells will be removed nonivasively by the same novel techniques as a rigorous test of their functional integration and performance. This level of specificity is unattainable by any existent methodology. Planned studies emphasize development and application of these mechanisms in vivo in order to model specific genetic or environmental perturbations of direct clinical relevance.
