, 2008) Different phases of adult neurogenesis are subject to re

, 2008). Different phases of adult neurogenesis are subject to regulation by pharmacological manipulations, mostly through various neurotransmitter systems (reviewed by Jang et al., 2008). Both the dentate gyrus and olfactory bulb are enriched with inputs from many brain regions that release different neurotransmitters and neuropeptides. Among classic neurotransmitters, glutamate, GABA, and probably acetylcholine directly regulate migration, maturation, integration, and survival of newborn

neurons. In most of other cases, it is not always clear whether pharmacological manipulations act by directly affecting neural precursors and newborn DAPT mouse neurons or through indirect modulation of the niche. Interestingly, antidepressants used in clinics, through changes in serotonin and nonrepinephrine levels, increase neural progenitor proliferation, accelerate dendritic development, and enhance survival of newborn neurons in the adult hippocampus (reviewed by Sahay and Hen, 2007 and Warner-Schmidt and Duman, 2006). Our understanding of extracellular cues that regulate targeted neuronal migration, axon/dendritic development, and synapse formation during adult neurogenesis is limited.

A number of adhesion molecules (e.g., β1-integrin, PSA-NCAM, Tenascin-R) and extracellular cues (e.g., GABA, NRGs and Slits) are known to regulate the stability, motility, or directionality of neuronal migration during adult SVZ neurogenesis (reviewed Selleckchem Kinase Inhibitor Library by Lledo et al., 2006 and Ming and Song, 2005). In the dentate gyrus, reelin signaling prevents new neurons from migrating into the hilus region; loss of reelin expression from local interneurons after pilocarpine-induced seizures may explain the ectopic hilar localization of new granule cells (Gong et al., 2007). Cell-cycle regulators, transcription factors, and epigenetic

factors are major intracellular regulators of adult neurogenesis (Zhao et al., 2008). Cell-cycle inhibitors, including p16, p21, and p53, play major roles in maintaining the quiescence of adult neural precursors; deletion of these factors leads to transient activation and subsequent depletion of the precursor pool. Sequential DNA ligase activation of different transcription factors ensures proper development of adult neural precursors. Sox2 is a major mediator of Notch signaling in maintaining the precursor pool in the adult SGZ (Ehm et al., 2010). Shh appears to be a direct target of Sox2 in neural precursors and deletion of Sox2 in adult mice results in a loss of hippocampal neurogenesis (Favaro et al., 2009). Orphan nuclear receptor TLX is also required for self-renewal and maintenance of neural precursors in the adult brain, probably through a canonical Wnt/β-catenin pathway (Qu et al., 2010).

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