eISSN: 2084-9885
ISSN: 1896-6764
Neuropsychiatria i Neuropsychologia/Neuropsychiatry and Neuropsychology
Bieżący numer Archiwum Artykuły zaakceptowane O czasopiśmie Bazy indeksacyjne Prenumerata Kontakt Zasady publikacji prac
SCImago Journal & Country Rank
vol. 2
Poleć ten artykuł:

Artykuł poglądowy
Modelowanie genetyki schizofrenii – nadmiar możliwości?

Barbara K. Lipska

Neuropsychiatria i Neuropsychologia 2007; 2, 2: 51–53
Data publikacji online: 2007/11/26
Plik artykułu:
- Modeling.pdf  [0.06 MB]
Pobierz cytowanie
JabRef, Mendeley
Papers, Reference Manager, RefWorks, Zotero
Many of the recently discovered schizophrenia candidate genes [e.g., COMT, GRM3, PPP3CC (calcineurin), DARPP32] have been associated with cognitive dysfunction, a symptom relatively resistant to current antipsychotic treatments and viewed as a core symptom of schizophrenia. The genetic animal models with mutations in the genes involved in brain development (e.g., DISC1, NRG1, DTNBP1) have provided insights into molecular mechanisms of abnormal neurodevelopment in schizophrenia. In particular, several recent studies on disruptions of the DISC1 gene in mice illustrate the great potential of the new genetic approaches but also signal the vast complexity of the problem.

The initial rationale for studying the effects
of mutations in DISC1 came from the discovery of the chromosomal translocation resulting in a breakpoint in the DISC1 gene that co-segregated with major mental illness in a Scottish family (reviewed by Porteous et al. 2006). These clinical findings were followed by a number of association studies, which reported that numerous single nucleotide polymorphisms (SNPs) across the gene were associated with schizophrenia and mood disorders and a variety of intermediate phenotypes, including hippocampal function and structure, prefrontal gray matter volume, memory and cognition, suggesting that other problems in the DISC1 gene may exist in other subjects/populations.

Animal models constructed to mimic partial loss of DISC1 function suggested that DISC1 is necessary to support development of the cerebral cortex as its loss resulted in impaired neurite outgrowth and the spectrum of behavioral abnormalities characteristic of major mental disorders (Kamiya et al. 2005; Koike et al. 2006; Clapcote et al. 2007; Hikida et al. 2007). Unexpectedly, however, another DISC1 knockdown model, achieved by RNA interference in single cells of the dentate gyrus, has recently demonstrated that DISC1 may also function as
a brake on neuronal development, and that its loss could lead to the opposite effects: dendritic overgrowth and accelerated synapse formation and maturation of newly generated neurons (Duan et al. 2007). Other emerging studies continue to reveal the highly complex nature of the DISC1 gene with multiple isoforms exhibiting different functions, perhaps depending on localization, timing and interactions with
a multitude of other gene products, some of which appear to confer susceptibility to mental illness in their own right, independently of DISC1 (Hennah et al. 2007; Hodgkinson et al. 2007; Kakiuchi
et al. 2007; Lipska et al. 2006; Millar et al. 2005; Pickard et al. 2007). Similar molecular complexity has also emerged in other susceptibility genes for schizophrenia, GRM3 (Sartorius et al. 2006), NRG1 (Tan et al. 2007) and COMT (Tunbridge et al. 2007). With the growing knowledge of transcript complexity, it becomes increasingly clear that subtle disturbances of isoform(s) of susceptibility gene products and intricate interactions between the susceptibility genes may account for the etiology of neuropsychiatric disorders. Research in animals will have a critical role in disentangling this web of interwoven genetic pathways.

1. Chen J, Lipska BK, Weinberger DR. Genetic mouse models of schizophrenia: from hypothesis-based to susceptibility gene-based models. Biol Psychiatry 2006; 59: 1180-1188.
2. Clapcote SJ, Lipina TV, Millar JK, et al. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 2007; 54: 387-402.
3. Costall B, Naylor RJ. Animal neuropharmacology and its prediction of clinical response. In: Schizophrenia. Hirsch SR, Weinberger DR (eds). Blackwell Science Ltd, Oxford, 1995; 401-424.
4. Duan X, Chang JH, Ge S, et al. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in adult brain. Cell 2007; 130: 1-13.
5. Hennah W, Tomppo L, Hiekkalinna T, et al. Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1. Hum Mol Genet 2007; 16: 453-462.
6. Hikida T, Jaaro-Peled H, Seshadri S, et al. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A 2007; 104: 14501-14506.
7. Hodgkinson CA, Goldman D, Ducci F, et al. The FEZ1 gene shows no association to schizophrenia in Caucasian or African American populations. Neuropsychopharmacology 2007; 32: 190-196.
8. Jones GH, Hernandez TD, Kendall DA, et al. Dopaminergic and serotonergic function following isolation rearing in rats: Study of behavioral responses and postmortem and in vivo neurochemistry. Pharm Biochem Behav 1992; 43: 17-35.
9. Kakiuchi C, Ishiwata M, Nanko S, et al. Association analysis of ATF4 and ATF5, genes for interacting-proteins of DISC1, in bipolar disorder. Neurosci Lett 2007; 417: 316-321.
10. Kamiya A, Kubo K, Tomoda T, et al. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 2005; 7: 1167-78.
11. Koike H, Arguello PA, Kvajo M, et al. Disc1 is mutated in the 129S6/SvEv strain and modulates working
Copyright: © 2007 Termedia Sp. z o. o. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
© 2019 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe