A central question in stem cell biology is how dynamic interactions between extrinsic niche signaling and intrinsic factors influence stem cell behavior and their development in vivo. Despite recent progress in identifying individual molecular players (Duan et al., 2008), little is known about the relationship between intrinsic and extrinsic signaling in regulating adult neurogenesis. Recent findings that reveal common processes of adult neurogenesis affected by DISC1 and GABA raise a tantalizing possibility that intrinsic factor DISC1 may regulate extrinsic GABA signaling. Here we employed a “single-cell” genetic approach to investigate the interaction between DISC1 and GABA signaling in regulating development of newborn dentate granule neurons during adult and early postnatal neurogenesis in vivo. We further explored whether these molecular interactions might contribute to mental illness by testing genetic interactions between single-nucleotide polymorphisms (SNPs) in DISC1 and SLC12A2 (which encodes human NKCC1) on risk for schizophrenia in three independent case control samples. Our study reveals a surprising role of developmental temporal dynamics and animal experience in determining the impact of genetic factors associated with schizophrenia and has important implications for understanding the pathogenesis of mental disorders.
