Characterisation of a mouse model of major mental illness

(1)University of Edinburgh, (2)University of Tubingen, (3)V.U University Amsterdam, (4) Sanofi

In a Scottish family, a balanced autosomal translocation t(1;11)(q42.1;q14.3) is linked to major mental illness (schizophrenia, bipolar disorder and recurrent depression) (1). This translocation directly disrupts the Disrupted in Schizophrenia 1 (DISC1) gene and its non-coding antisense partner DISC2 on chromosome 1 (2). A third gene, DISC1FP1, is disrupted on chromosome 11 (3). We aim to characterize a mouse model of the translocation in which the 3’ half of the endogenous Disc1 gene, has been replaced with a segment of human chromosome 11 containing the relevant exons of DISC1FP1, thus mimicking the effect of the translocation upon DISC1. Here, we explore the brain structure of this mouse model using histological techniques and examine differential RNA expression using RNA sequencing (RNAseq).

At nine weeks, five male littermate trios (wild type, heterozygous, homozygous) were perfused for histological analysis. Two 10um sections from equivalent positions in the forebrain and midbrain were analysed per animal. For the RNAseq, RNA was prepared from hippocampus and cortex taken from eight mice (4 males and 4 females) per genotype at nine weeks of age.

The ventricle’s areas are significantly larger (p=0.041) in the heterozygous mice compared to the homozygous mice. Cortical area and cellular density are unaltered, which might indicate that neuronal properties are affected. We found multiple differences between the heterozygotes and WT RNA expression, such as modified synaptic mechanisms, vesicle transport and receptor expression, which support this idea. The translocation leads to enlargement of the lateral ventricles in heterozygous mice which is frequently observed in schizophrenic patients (4). The RNAseq indicates that the translocation affects gene expression in important systems which are also affected in the human carrier iPSCs. Further studies are needed to asses weather this model could be used as a schizophrenia-like model.

References

1. Blackwood, D. H. R., Fordyce, A., Walker, M. T., Clair, D. M. S., Porteous, D. J., & Muir, W. J. (2001). Schizophrenia and Affective Disorders — Cosegregation with a Translocation at Chromosome 1q42 That Directly Disrupts Brain-Expressed Genes : Clinical and P300 Findings in a Family, 428–433.
2. Millar, J. K., Wilson-annan, J. C., Anderson, S., Christie, S., Martin, S., Semple, C. A. M., … Porteous, D. J. (2000). Disruption of two novel genes by a translocation co-segregating with schizophrenia, 9(9), 1415–1424.
3. Eykelenboom, J. E., Briggs, G. J., Bradshaw, N. J., Soares, D. C., Ogawa, F., Christie, S., … Millar, J. K. (2012). A t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric DISC1 transcripts that encode structurally altered, deleterious mitochondrial proteins. Human Molecular Genetics, 21(15), 3374–86. doi:10.1093/hmg/dds169
4. Pletnikov, M. V, Ayhan, Y., Xu, Y., Nikolskaia, O., Ovanesov, M., Huang, H., … Ross, C. a. (2008). Enlargement of the lateral ventricles in mutant DISC1 transgenic mice. Molecular Psychiatry, 13(2), 115. doi:10.1038/sj.mp.4002144

Funded by: Marie Curie

* entered into the PhD student poster competition