The seminal identification of mutations in DISC1 associated with schizophrenia and other psychiatric disorders raises several obvious questions: what does the DISC1 protein normally do? What are its biochemical and cellular functions, and what processes are affected by its mutation? How do defects in these cellular processes ultimately lead to altered brain function and psychopathology? Which brain systems are affected and how? Similar questions could be asked for the growing number of other genes that have been implicated by the identification of putatively causal mutations, including NRG1, ERBB4, NRXN1, CNTNAP2, and many copy number variants. Finding the points of biochemical or phenotypic convergence for these proteins or mutations may be key to understanding how mutations in so many different genes can lead to a similar clinical phenotype and to suggesting points of common therapeutic intervention.

The papers by Kim et al. and Enomoto et al. add more detail to the complex picture of the biochemical interactions of DISC1 and its diverse cellular functions. The links with Akt and PTEN signaling are especially interesting, given the previous implication of these proteins in schizophrenia and autism. Akt, in particular, may provide a link between Nrg1/ErbB4 signaling and DISC1 intracellular functions.

These studies also reinforce the importance of DISC1 and its interacting partners in neurodevelopment, specifically in cell migration and axonal extension. In particular, they highlight the roles of these proteins in postnatal hippocampal development and adult hippocampal neurogenesis. They also raise the question of which extracellular signals and receptors regulate these processes through these signalling pathways. The Nrg1/ErbB4 pathway has already been implicated, but there are a multitude of other cell migration and axon guidance cues known to regulate hippocampal development, some of which, for example, semaphorins, signal through the PTEN pathway.

Whether or how disruptions in these developmental processes contribute to psychopathology also remains unclear. It seems likely that the effects of mutations in any of these genes will be highly pleiotropic and have effects in many brain systems. The reported pathology in schizophrenia is not restricted to hippocampus but extends to cortex, thalamus, cerebellum, and many other regions. Similarly, while the cognitive deficits receive a justifiably large amount of attention, given that they may have the most clinical impact, motor and sensory deficits are also a stable and consistent part of the syndrome that must be explained. Pleiotropic effects on prenatal and postnatal development, as well as on adult processes, may actually be the one common thread characterizing the genes so far implicated. These new papers represent the first steps in the kinds of detailed biological studies that will be required to make explanatory links from mutations, through biochemical and cellular functions, to effects on neuronal networks and ultimately psychopathology.

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DISC1 disruption by chromosomal translocation cosegregates with several neuropsychiatric disorders, including schizophrenia (Blackwood et al., 2001; Millar et al., 2000). Recent attention has focused on the effects of DISC1 on the structure and function of the dentate gyrus, one of the few brain regions that exhibit neurogenesis throughout life. The downregulation of DISC1 has several deleterious effects on the dentate gyrus, including aberrant neuronal migration (Duan et al., 2007). However, the mechanisms through which DISC1 regulates the structure and function of the dentate gyrus remain unknown. The dentate gyrus and its output to the CA3 area, the mossy fiber, show several abnormalities in schizophrenia and other neuropsychiatric diseases (Kobayashi, 2009). Thus, understanding how a gene associated with neuropsychiatric disease, DISC1, mechanistically impacts the dentate gyrus is an important question with much clinical relevance.

The recent papers by Kim et al. and Enomoto et al. characterize an interaction between DISC1 and girdin (also known as KIAA1212), and reveal how girdin, and the interaction between DISC1 and girdin, impact axon development, dendritic development, and the proper positioning of newborn neurons in the dentate gyrus. Girdin normally stimulates the function of AKT (Anai et al., 2005), and Kim et al. show that DISC1 binds to girdin and inhibits its function. Thus, the loss of DISC1 leaves girdin unopposed, resulting in excessive AKT signaling. Indeed, the developmental defects in neurons lacking DISC1 can be rescued by pharmacologically blocking the activation of an AKT downstream target. However, as shown by Enomoto et al., the loss of girdin produces deleterious effects on neuronal morphology, suggesting that a proper balance of girdin function is crucial.

Collectively, these studies thoroughly characterize the interaction between DISC1 and girdin, and shed much light on the consequences of this interaction on neuronal morphology as well as on the positioning of neurons in the dentate gyrus. The role of girdin in the pathology of neuropsychiatric diseases is unknown, and remains an interesting question for the future. Characterizing the molecules that act up- or downstream of DISC1 remains an important area of investigation and could aid the development of pharmacological interventions in the future. It’s intriguing that DISC1 acting through girdin regulates the activity of AKT as AKT1 was previously identified as a schizophrenia risk gene (Emamian et al., 2004). This suggests a convergence of multiple schizophrenia-associated genes in a shared pathway, and thus it will be important to determine if the DISC1-girdin-AKT1 pathway is particularly vulnerable in neuropsychiatric disorders.

References:

Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ. Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet . 2001 Aug 1 ; 69(2):428-33. Abstract

Millar JK, Christie S, Semple CA, Porteous DJ. Chromosomal location and genomic structure of the human translin-associated factor X gene (TRAX; TSNAX) revealed by intergenic splicing to DISC1, a gene disrupted by a translocation segregating with schizophrenia. Genomics . 2000 Jul 1 ; 67(1):69-77. Abstract

Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell . 2007 Sep 21 ; 130(6):1146-58. Abstract

Kobayashi K. Targeting the hippocampal mossy fiber synapse for the treatment of psychiatric disorders. Mol Neurobiol . 2009 Feb 1 ; 39(1):24-36. Abstract

Anai M, Shojima N, Katagiri H, Ogihara T, Sakoda H, Onishi Y, Ono H, Fujishiro M, Fukushima Y, Horike N, Viana A, Kikuchi M, Noguchi N, Takahashi S, Takata K, Oka Y, Uchijima Y, Kurihara H, Asano T. A novel protein kinase B (PKB)/AKT-binding protein enhances PKB kinase activity and regulates DNA synthesis. J Biol Chem . 2005 May 6 ; 280(18):18525-35. Abstract

Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet . 2004 Feb 1 ; 36(2):131-7. Abstract

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