NEUROGENESIS IN DISORDERS OF BRAIN DEVELOPMENT

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DESCRIPTION (adapted from applicant's abstract): The cause of mental retardation in Down syndrome (DS) is not understood but is thought to result, at least in part, from defective brain development during the embryonic period when neurons of the cerebral cortex are being generated. The trisomy 16 (Ts16) mouse shares a common genetic defect with DS and may be useful for studying the mechanisms underlying abnormal embryonic development of the cerebral cortex. Prenatal generation of postmitotic neurons in the Ts16 mouse cortex is delayed and subplate neurons are born concurrently with cortical plate neurons rather than preceding them as in the normal cortex. These abnormalities in the timing of Ts16 neurogenesis may lead to defective connectivity in the mature brain; similar defects during the prenatal development of the human brain may contribute to mental retardation in DS. Proliferation of neuroprogenitor cells (neuroblasts) and the decision of daughter cells to leave the cell cycle, which ultimately control the timing of neurogenesis, are regulated by neurotransmitters and growth factors such as glutamate and brain derived neurotrophic factor (BDNF). Ts16 neuroblasts fail to respond to glutamate and BDNF, raising the possibility that this signaling defect may underlie delayed neurogenesis in Ts16. The molecular basis for defects in the regulation of Ts16 neurogenesis will be studied in a) dissociated cell cultures of neuroblasts and b) organotypic slices from Ts16 and littermate euploid cortex. Both of these preparations enable not only the direct application of putative regulators of neurogenesis and of inhibitors of signaling pathways, but also direct measurement of proliferation, cell death and intracellular levels of Ca2+, a key modulator of proliferation, neuronal differentiation and migration. Experiments in organotypic slices will enable these processes to be analyzed in a structurally intact cortex and will allow the behavior of anatomically-distinct populations of neuroblasts and postmitotic neurons to be distinguished. The overall goals of this research project are to identify the signaling defects that lead to abnormal neurogenesis in the Ts16 mouse cerebral cortex and, at the same time, to determine the molecular signaling mechanisms underlying the control of neurogenesis in the normal brain.