A Common Glial-Neuronal Progenitor in Postnatal Brain

Children'S Research Institute, Washington DC

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Abstract

DESCRIPTION (provided by applicant): Neurogenesis continues to occur in restricted areas of the postnatal and adult brain, and is modulated by environmental stimuli. Newly generated neurons in the adult brain can propagate action potentials and are synaptically connected. The origin of these neurons and the lineage potential of neural progenitor cells found in the adult brain are still poorly understood. In this proposal we will use a transgenic mouse line expressing enhanced green fluorescent protein (EGFP) under the control of the myelin gene promoter 2'-3' cyclic nucleotide 3-phosphodiesterase (CNP). We have recently found that CNP-EGFP+ progenitor cells expressing the chondroitin proteoglycan NG2 and isolated from the postnatal brain of these mice can generate neurons, oligodendrocytes and astrocytes. By using a multidisciplinary cellular, molecular and electrophysiological approach, we will determine whether the lineage and cell specification potential of perinatal NG2+/CNP-EGFP+ cells is conserved throughout postnatal development and in the adult brain in vitro and in vivo. We will define the identity of neurons generated from perinatal and adult NG2+/CNP-EGFP+ progenitor cells. Because of their well-established involvement in neural cell specification during development, we will also study the role of Notch receptor pathways in the differentiation of postnatal NG2+/CNP-EGFP+ cells to neurons. We have also accumulated experimental evidence indicating that, in the hippocampus in vivo, NG2+/CNP-EGFP+ cells can generate new glutamate decarboxylase+ (GAD+), dlx+ GABAergic neurons throughout the entire postnatal period into adulthood. We will characterize these EGFP+ neurons by using anatomical, electrophysiological and imunocytochemical approaches. By analyzing their electrophysiological properties, including their integration into synaptic circuits, we will assess their functional development. Finally, we will determine if these differentiated neurons display synaptic plasticity in the hippocampus during development. Together these studies will not only provide new insights into adult neurogenesis, but will also help design strategies to induce neuronal repair by triggering generation of new neurons from a selected population of endogenous glial-neuronal progenitors.