Minor allele carriers of the L607F variant in both healthy individual and schizophrenia patients displayed reduced gray matter density in the superior frontal gyrus and anterior cingulate gyrus, and also experienced greater positive symptoms (Szeszko et al., 2008). Interestingly, a recent study from Rapoport and colleagues reported both S704C and L607F variants affect cortical thickness in developing children and adolescents (Raznahan et al., 2010). Selleck I BET151 Here, the authors determined complex interplay between S704C, L607F, and cortical thickness, suggesting these

variants functionally interact to regulate the structure of the developing brain. Together, these studies highlight that common DISC1 variants play an important role in regulating brain structure, function, and neuropsychiatric behavior. However, it is still unclear how these

polymorphisms lead to changes in brain structure and, moreover, whether they disrupt DISC1 signaling pathways that contribute to these effects. Given the different brain structural and functional changes associated with common DISC1 Compound C manufacturer polymorphisms, we hypothesized these effects were due to deleterious effects on brain development via disruption of specific signaling pathways. Various studies have uncovered a number of brain development events and signaling pathways that critically involve DISC1. For example, some of the processes DISC1 regulates includes neurogenesis, neuronal migration, axon/dendrite growth, synaptogenesis, adult neuron generation and synaptic integration, dopaminergic neuron function, and cell-cell adhesion (Enomoto et al., 2009, Hayashi-Takagi et al., 2010, Kamiya et al., 2005, Kamiya et al., 2006, Kim et al., 2009, Lipina et al., 2010b, Mao et al., 2009, Niwa et al., 2010, Pletnikov et al., 2007 and Singh et al., 2010).

This is further complicated by the number of DISC1-dependent pathways that have been identified to date, including signaling via Lis1/Ndel1, phosphodiesterase 4/cyclic adnosine monophosphate (cAMP), interaction with growth neuregulin, amyloid precursor protein (APP), Akt/Girdin signaling, and Rac1, and our lab recently reported that DISC1 modulates canonical Wnt signaling via GSK3β and Dixdc1 (Enomoto et al., 2009, Jaaro-Peled et al., 2009, Kamiya et al., 2006, tuclazepam Kim et al., 2009, Mao et al., 2009, Millar et al., 2005, Shinoda et al., 2007 and Young-Pearse et al., 2010). The finding that DISC1 directly inhibits GSK3β is interesting given that the common mood stabilizer drug lithium, and the schizophrenia risk gene Akt, also inhibit GSK3β which results in activation of canonical Wnt signaling, suggesting it may be an important target in psychiatric disease. Here, we present evidence that human DISC1 variants have a deleterious impact on two brain development events, neurogenesis and neuronal migration, via different signaling pathways.