Skip to main content Accessibility help
×
Home

Catecholaminergic neuronal network dysfunction in the frontal lobe of a genetic mouse model of schizophrenia

  • Shuji Iritani (a1), Hirotaka Sekiguchi (a1), Chikako Habuchi (a1), Youta Torii (a1), Keisuke Kuroda (a2), Kozo Kaibuchi (a2) and Norio Ozaki (a1)...

Abstract

Background

The precise aetiology of schizophrenia remains unclear. The neurodevelopmental hypothesis of schizophrenia has been proposed based on the accumulation of genomic or neuroimaging studies.

Objective

In this study, we examined the catecholaminergic neuronal networks in the frontal cortices of disrupted-in-schizophrenia 1 (DISC1) knockout (KO) mice, which are considered to be a useful model of schizophrenia.

Methods

Six DISC1 homozygous KO mice and six age-matched littermates were used. The animals’ brains were cut into 20-μm-thick slices, which were then immunohistochemically stained using an anti-tyrosine hydroxylase (TH) monoclonal antibody.

Results

The TH-immunopositive fibres detected in the orbitofrontal cortices of the DISC1 KO mice were significantly shorter than those seen in the wild-type mice.

Conclusion

These neuropathological findings indicate that the hypofrontal symptoms of schizophrenia are associated with higher mental function deficiencies or cognitive dysfunction such as a loss of working memory.

Copyright

Corresponding author

Shuji Iritani, Department of Psychiatry, Nagoya University Graduate School of Medicine, Tsurumai 65, Shouwa, Nagoya, Aichi 466-8550, Japan. Tel: +8 152 744 2282; Fax: +8 152 744 2293; E-mail: iritani@med.nagoya-u.ac.jp

References

Hide All
1. Owen, MJ, O’Donovan, MC, Thapar, A, Craddock, N. Neurodevelopmental hypothesis of schizophrenia. Br J Psychiatry 2011;198:173175.
2. Iritani, S. What happens in the brain of schizophrenia patients?: an investigation from the viewpoint of neuropathology. Nagoya J Med Sci 2013;75:1128.
3. Harrison, PJ. Schizophrenia susceptibility genes and neurodevelopment. Biol Psychiatry 2007;61:11191120.
4. Millar, JK, Wilson-Annan, JC, Anderson, S et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 2000;9:14151423.
5. Ishizuka, K, Paek, M, Kamiya, A, Sawa, A. A review of Disrupted-In-Schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions. Biol Psychiatry 2006;59:11891197.
6. Kamiya, A, Kubo, K, Tomoda, T et al. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 2005;7:11671178.
7. Jaaro-Peled, H, Niwa, M, Foss, CA et al. Subcortical dopaminergic deficits in a DISC1 mutant model: a study in direct reference to human molecular brain imaging. Hum Mol Genet 2013;22:15741580.
8. Lipina, TV, Roder, JC. Disrupted-In-Schizophrenia-1 (DISC1) interactome and mental disorders: impact of mouse models. Neurosci Biobehav Rev 2014;45:271294.
9. Lee, FH, Fadel, MP, Preston-Maher, K et al. Disc1 point mutations in mice affect development of the cerebral cortex. J Neurosci 2011;31:31973206.
10. Singh, KK, De Rienzo, G, Drane, L et al. Common DISC1 polymorphisms disrupt Wnt/GSK3beta signaling and brain development. Neuron 2011;72:545558.
11. Ishizuka, K, Kamiya, A, Oh, EC et al. DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature 2011;473:9296.
12. Singh, KK, Ge, X, Mao, Y et al. Dixdc1 is a critical regulator of DISC1 and embryonic cortical development. Neuron 2010;67:3348.
13. Niwa, M, Kamiya, A, Murai, R et al. Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. Neuron 2010;65:480489.
14. Pratt, JA, Winchester, C, Egerton, A, Cochran, SM, Morris, BJ. Modelling prefrontal cortex deficits in schizophrenia: implications for treatment. Br J Pharmacol 2008;153(Suppl. 1):S465S470.
15. Kanahara, N, Sekine, Y, Haraguchi, T et al. Orbitofrontal cortex abnormality and deficit schizophrenia. Schizophr Res 2013;143:246252.
16. Howes, OD, Kapur, S. The dopamine hypothesis of schizophrenia: version III – the final common pathway. Schizophr Bull 2009;35:549562.
17. Kuroda, K, Yamada, S, Tanaka, M et al. Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Hum Mol Genet 2011;20:46664683.
18. Nakai, T, Nagai, T, Wang, R et al. Alterations of GABAergic and dopaminergic systems in mutant mice with disruption of exons 2 and 3 of the Disc1 gene. Neurochem Int 2014;74:7483.
19. Berretta, S, Pantazopoulos, H, Markota, M, Brown, C, Batzianouli, ET. Losing the sugar coating: potential impact of perineuronal net abnormalities on interneurons in schizophrenia. Schizophr Res 2015, doi:10.1016/j.schres.2014.12.040.
20. Du, J, Quan, M, Zhuang, W et al. Hippocampal volume reduction in female but not male recent abstinent methamphetamine users. Behav Brain Res 2015;289:7883.
21. Kambeitz, J, Abi-Dargham, A, Kapur, S, Howes, OD. Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies. Br J Psychiatry 2014;204:420429.
22. Sekiguchi, H, Iritani, S, Habuchi, C et al. Impairment of the tyrosine hydroxylase neuronal network in the orbitofrontal cortex of a genetically modified mouse model of schizophrenia. Brain Res 2011;1392:4753.
23. Perez-Costas, E, Melendez-Ferro, M, Rice, MW, Conley, RR, Roberts, RC. Dopamine pathology in schizophrenia: analysis of total and phosphorylated tyrosine hydroxylase in the substantia nigra. Front Psychiatry 2012;3:31.
24. Horiguchi, M, Ohi, K, Hashimoto, R et al. Functional polymorphism (C-824T) of the tyrosine hydroxylase gene affects IQ in schizophrenia. Psychiatry Clin Neurosci 2014;68:456462.
25. Hu, J, Chan, LF, Souza, RP et al. The role of tyrosine hydroxylase gene variants in suicide attempt in schizophrenia. Neurosci Lett 2014;559:3943.
26. O’Tuathaigh, CM, Desbonnet, L, Waddington, JL. Genetically modified mice related to schizophrenia and other psychoses: seeking phenotypic insights into the pathobiology and treatment of negative symptoms. Eur Neuropsychopharmacol 2014;24:800821.
27. Wu, Q, Li, Y, Xiao, B. DISC1-related signaling pathways in adult neurogenesis of the hippocampus. Gene 2013;518:223230.
28. van Veelen, NM, Vink, M, Ramsey, NF, van Buuren, M, Hoogendam, JM, Kahn, RS. Prefrontal lobe dysfunction predicts treatment response in medication-naive first-episode schizophrenia. Schizophr Res 2011;129:156162.
29. Puig, MV, Miller, EK. Neural substrates of dopamine D2 receptor modulated executive functions in the monkey prefrontal cortex. Cereb Cortex 2015;25:29802987.
30. Harrison, PJ, Weinberger, DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005;10:4068.

Keywords

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed