New neurons are generated from neural progenitors throughout life in discrete regions of the adult mammalian central nervous system (CNS), including humans. Adult neurogenesis recapitulates the whole process of neuronal development in a mature CNS environment, including proliferation and fate specification of adult neural progenitors, neuronal differentiation, maturation, migration, guidance and synaptic integration of newborn neurons. The molecular mechanisms that regulate the distinct steps of adult neurogenesis are largely unknown. Accumulating evidence suggests that adult neurogenesis is involved/altered in many physiological and pathological conditions, such as learning and memory, epilepsy, mental disorders and degenerative neurological diseases. Understanding the molecular mechanisms for adult neurogenesis may provide clues into the etiology and pathology of these mental disorders and diseases, and more importantly, may lead to novel therapies. A better understanding of adult neurogenesis may also lead to novel strategies to functionally replace damaged or lost neurons after injury or degenerative neurological disease using neurons derived from stem cells, including both embryonic stem cells and adult neural stem cells. My laboratory has been investigating neurogenesis in the dentate gryrus of adult mice as a model system to understand mechanisms regulating neural development in the adult CNS environment. We have established a "single-cell genetic approach" to specifically label and genetically manipulate newborn cells during adult neurogenesis in vivo. We have characterized the neuronal development of newborn granule cells in the hippocampus of adult mice with immunocytochemistry, electron microscopy, live imaging and electrophysiology. We also made the original discovery that GABA, a major neurotransmitter in the adult brain, depolarizes newborn neurons during their initial development in the adult hiippocampus and, furthermore, such depolaization appears to be essential for the inetgration of new neurons. In the current project, we propose to use the "singe-cell genetic approach" to investigate the functional roles and underlying mechanisms of GABA in regulating distinct steps of adult neurogenesis, including differentiation, maturation, survival, migration, axon and dendritic development, formation of synaptic inputs and outputs, and synaptic plasticity of neuronal progeny in the adult brain in vivo. These studies will provide the groundwork for future goals in understanding the mechanism and function of adult neurogenesis under physiological and pathological conditions and may lead to novel strategies for potential neuronal replacement therapies in the adult CNS. PUBLIC HEALTH RELEVANCE: The project aims at understanding how new neurons derived from neural stem cells become integrated into the existing neuronal ciruitry in the adult brain. Findings from these studies may also lead to novel strategies to functionally replace damaged or lost neurons after injury or degenerative neurological disease either using neurons derived from endogenous stem cells or transplantation of neurons from exogenous stem cells.