DISC1 Puts the Brakes on Neurogenesis

The gene DISC1 (Disrupted-in-Schizophrenia 1) is a leading candidate gene for schizophrenia. In this issue, Duan et al., 2007Duan X. Chaung J.H. Ge S. Faulkner R.L. Kim J.Y. Kitabatake Y. Liu X.-b. Yang C.-H. Jordan J.D. Ma D.K. et al.Cell. 2007; (this issue)Google Scholar present evidence implicating DISC1 in the maturation and integration of newly generated neurons in the adult mouse hippocampus. Surprisingly, DISC1 appears to have opposite effects on neurogenesis during development and in adulthood. The gene DISC1 (Disrupted-in-Schizophrenia 1) is a leading candidate gene for schizophrenia. In this issue, Duan et al., 2007Duan X. Chaung J.H. Ge S. Faulkner R.L. Kim J.Y. Kitabatake Y. Liu X.-b. Yang C.-H. Jordan J.D. Ma D.K. et al.Cell. 2007; (this issue)Google Scholar present evidence implicating DISC1 in the maturation and integration of newly generated neurons in the adult mouse hippocampus. Surprisingly, DISC1 appears to have opposite effects on neurogenesis during development and in adulthood. Initial evidence for the involvement of the DISC1 (Disrupted-in-Schizophrenia 1) gene in schizophrenia was based primarily on a large Scottish pedigree where the gene was disrupted by a chromosomal translocation. Several other linkage and association studies also connect DISC1 to schizophrenia and to other psychotic and affective disorders (Mackie et al., 2007Mackie S. Millar J.K. Porteous D.J. Curr. Opin. Neurobiol. 2007; 17: 95-102Crossref PubMed Scopus (84) Google Scholar). Thus understanding the role of the DISC1 gene product could reveal insights into the pathophysiology of psychiatric illness. Analysis of DISC1 function supports a role in regulating neuronal migration and structural plasticity. DISC1 expression is highest during the neurogenic period of development and in neurogenic regions in the adult rodent brain. Although much work has focused on the involvement of DISC1 in neurogenesis during development, new work by Duan et al., 2007Duan X. Chaung J.H. Ge S. Faulkner R.L. Kim J.Y. Kitabatake Y. Liu X.-b. Yang C.-H. Jordan J.D. Ma D.K. et al.Cell. 2007; (this issue)Google Scholar reveals an unexpected role for DISC1 in the maturation of neurons born during adulthood. During embryonic development DISC1 regulates neuronal migration and structural plasticity, apparently through its involvement in microtubule dynamics (Kamiya et al., 2005Kamiya A. Kubo K. Tomoda T. Takaki M. Youn R. Ozeki Y. Sawamura N. Park U. Kudo C. Okawa M. et al.Nat. Cell Biol. 2005; 7: 1167-1178Crossref PubMed Scopus (427) Google Scholar). DISC1 interacts with members of the dynein microtubule motor complex, including LIS1 and NudEL, in a pathway regulated by Reelin (another protein implicated in schizophrenia). Both LIS1 and NudEL are involved in the control of microtubule assembly by the centrosome and hence neuritic growth and neuronal migration (Shu et al., 2004Shu T. Ayala R. Nguyen M.D. Xie Z. Gleeson J.G. Tsai L.H. Neuron. 2004; 44: 263-277Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar). Moreover, mutations in LIS1 are linked to lissencephaly, a disease of aberrant neuronal migration during cortical neurogenesis. Thus, mutations in several genes that encode proteins of the dynein complex are associated with neurodevelopmental diseases, including schizophrenia. Expression of C terminally truncated DISC1 in cell culture, in attempts to mimic the Scottish pedigree translocation, results in dissociation of the dyenin complex from the centrosome, suggesting a loss-of-function phenotype (Ross et al., 2006Ross C.A. Margolis R.L. Reading S.A. Pletnikov M. Coyle J.T. Neurobiology of schizophrenia.Neuron. 2006; 52: 139-153Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar). Furthermore, decreasing DISC1 expression in utero by RNA interference (RNAi) greatly limits the radial migration of neuroblasts toward their cortical destinations (Kamiya et al., 2005Kamiya A. Kubo K. Tomoda T. Takaki M. Youn R. Ozeki Y. Sawamura N. Park U. Kudo C. Okawa M. et al.Nat. Cell Biol. 2005; 7: 1167-1178Crossref PubMed Scopus (427) Google Scholar). In addition, expression of truncated DISC1 in cultured cells diminishes neuritic sprouting and knockdown by RNAi in vivo decreases the complexity of dendritic branching. Thus, during cortical neurogenesis, DISC1 appears to facilitate neuronal migration and neuritic sprouting. The experiments presented by Duan et al., 2007Duan X. Chaung J.H. Ge S. Faulkner R.L. Kim J.Y. Kitabatake Y. Liu X.-b. Yang C.-H. Jordan J.D. Ma D.K. et al.Cell. 2007; (this issue)Google Scholar in adult mice paint a different picture for the role of DISC1 in adult neurogenesis. By using an oncoretrovirus-based RNAi approach, the investigators asked whether DISC1 is also involved in the maturation of adult-born neurons in the hippocampus. In stark contrast to cortical neurogenesis during development, interference with DISC1 expression in hippocampal progenitors in adults resulted in an increase in neuronal migration. Some cells deficient in DISC1 even exited the granule cell layer, where adult-born neurons are normally confined. The DISC1-deficient cells also exhibited an increase in neuritic sprouting with dendritic redundancy and physiologic and morphologic signs of accelerated synaptic maturation. Although prior data implicate DISC1 in facilitating neuronal maturation during cortical neurogenesis, the current experiments make a strong case for negative regulation of neuronal maturation by DISC1 in the adult hippocampus. Moreover, partial knockdown of NudEL potentiated the DISC1 knockdown phenotype of the adult-born neurons. Therefore, although DISC1 appears to have opposite effects on neuronal maturation in embryonic and adult neurogenesis, the cellular mechanisms targeted by DISC1 are likely to be at least partially conserved. Two major differences between prior studies and the current one that may underlie the seemingly paradoxical roles of DISC1 in neuronal maturation are the brain structure under study and age of the animals (Figure 1). Duan and colleagues studied adult neurogenesis in the hippocampal dentate gyrus and compared it to embryonic cortical neurogenesis in the subventricular zone. Embryonic neurogenesis in the subventricular zone is followed by radial migration into the cortical lamina. However, adult-born neurons in the subventricular zone undergo a more tangential type of migration toward the olfactory bulb. Neurogenesis in the dentate gyrus also seems to differ during the embryonic and adult stages. Neurons of the granule cell layer born during embryogenesis were suggested to establish what eventually becomes the external layers of the dentate gyrus by a more tangential migration from the neuroepithelium (Altman and Bayer, 1990Altman J. Bayer S.A. J. Comp. Neurol. 1990; 301: 365-381Crossref PubMed Scopus (704) Google Scholar). Neurons born during early postnatal periods become distributed throughout the dentate gyrus, whereas those born in adulthood originate in the subgranular zone and seldom leave the inner half of the granule cell layer. Thus, the migratory pathways of neurons of the granule cell layer born in development differ greatly from those born in adulthood. The investigators propose that regional differences in the gradients of guidance cues between the subventricular zone and subgranular zone may contribute to the opposing functions of DISC1 during development and in adulthood (see Figure S4 in Duan et al., 2007Duan X. Chaung J.H. Ge S. Faulkner R.L. Kim J.Y. Kitabatake Y. Liu X.-b. Yang C.-H. Jordan J.D. Ma D.K. et al.Cell. 2007; (this issue)Google Scholar). Additionally, the animal's age could dictate differences in guidance cue gradients and direct whether DISC1 puts the gas or the brakes on neuronal maturation. Genetic studies convincingly implicate DISC1 in the biology of schizophrenia and other psychiatric illnesses. Individuals with DISC1 mutations exhibit physiological phenotypes associated with schizophrenia, such as deficits in evoked response potentials and decreased activity in the hippocampus during working memory tasks as visualized by functional magnetic resonance imaging (fMRI). Recent postmortem studies indicated that the number of dividing cells is decreased in the subgranular zone of individuals with schizophrenia (Ross et al., 2006Ross C.A. Margolis R.L. Reading S.A. Pletnikov M. Coyle J.T. Neurobiology of schizophrenia.Neuron. 2006; 52: 139-153Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar). This led to the speculation that defects in neurogenesis in the adult hippocampus may be involved in the disorder (Reif et al., 2006Reif A. Fritzen S. Finger M. Strobel A. Lauer M. Schmitt A. Lesch K.P. Mol. Psychiatry. 2006; 11: 514-522Crossref PubMed Scopus (488) Google Scholar). However, in rodents, even complete ablation of neurogenesis in the adult hippocampus produces only subtle deficits on very specific behavioral tasks (Dranovsky and Hen, 2006Dranovsky A. Hen R. Biol. Psychiatry. 2006; 59: 1136-1143Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar, Saxe et al., 2007Saxe M.D. Malleret G. Vronskaya S. Mendez I. Garcia A.D. Sofroniew M.V. Kandel E.R. Hen R. Proc. Natl. Acad. Sci. USA. 2007; 104: 4642-4646Crossref PubMed Scopus (193) Google Scholar). Thus, the contribution of neurogenesis in the adult hippocampus to behavior remains a controversial topic. Can loss-of-function mutations in DISC1 account for the schizophrenia phenotype by accelerating the normal maturation of adult-born neurons? Given that DISC1 regulates maturation of neurons generated during early development as well as in adulthood, the anatomical sequelae of DISC1 mutations are likely to be more pronounced during early development, when neurogenesis is more prevalent. Thus, the prevailing view of the etiology of schizophrenia as a developmental disorder hypothesizes that there are early defects in cortical neurogenesis (Ross et al., 2006Ross C.A. Margolis R.L. Reading S.A. Pletnikov M. Coyle J.T. Neurobiology of schizophrenia.Neuron. 2006; 52: 139-153Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar). A migratory deficit during early development would also be easier to reconcile with the fact that the pathology associated with schizophrenia is not restricted to the hippocampus. Dilated ventricles, decreased volume of the prefrontal cortex, loss of inhibitory interneuron subtypes, and evidence of synaptic dysfunction have all been reported in the illness. Although current evidence links early development to schizophrenia, a role for adult-born neurons in the pathophysiology of schizophrenia is an intriguing new hypothesis. Future behavioral experiments with pharmacological validation will inform whether adult neurogenesis is also involved in the pathophysiology of schizophrenia. The behavioral sequelae of DISC1 mutations have thus far been explored only with developmental interventions in rodents. A recent provocative study reported that two mutations in different regions of the DISC1 gene can produce very different behavioral phenotypes (Clapcote et al., 2007Clapcote S.J. Lipina T.V. Millar J.K. Mackie S. Christie S. Ogawa F. Lerch J.P. Trimble K. Uchiyama M. Sakuraba Y. et al.Neuron. 2007; 54: 387-402Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar). One mutation led mice to exhibit schizophrenia-like phenotypes that were reversible by treatment with antipsychotics but not antidepressants. The other mutation resulted in helpless behaviors that were reversed by treatment with antidepressants but not antipsychotics. Similar behavioral analysis following manipulation of postnatal neurogenesis and DISC1 function are needed to support the speculation that DISC1 could contribute to schizophrenia by regulating the maturation of adult-born neurons.