Altered brain gene expression but not steroid biochemistry in a genetic mouse model of neurodevelopmental disorder

Trent, Simon; Fry, Jonathan P; Ojarikre, Obah A; Davies, William

Abstract

Background
The 39,XY*O mouse, which lacks the orthologues of the ADHD and autism candidate genes STS (steroid sulphatase) and ASMT (acetylserotonin O-methyltransferase), exhibits behavioural phenotypes relevant to developmental disorders. The neurobiology underlying these phenotypes is unclear, although there is evidence for serotonergic abnormalities in the striatum and hippocampus.

Methods
Using microarray and quantitative gene expression analyses, and gas chromatography–mass spectrometry, we compared brain gene expression and steroid biochemistry in wildtype (40,XY) and 39,XY*O adult mice to identify non-obvious genetic and endocrine candidates for between-group differences in behaviour and neurochemistry. We also tested whether acute STS inhibition by COUMATE in wildtype (40,XY) adult male mice recapitulated any significant gene expression or biochemical findings from the genetic comparison. Data were analysed by unpaired t-test or Mann Whitney U-test depending on normality, with a single factor of KARYOTYPE.

Results
Microarray analysis indicated seven robust gene expression differences between the two groups (Vmn2r86, Sfi1, Pisd-ps1, Tagap1, C1qc, Metap1d, Erdr1); Erdr1 and C1qc expression was significantly reduced in the 39,XY*O striatum and hippocampus, whilst the expression of Dhcr7 (encoding 7-dehydrocholesterol reductase, a modulator of serotonin system development), was only reduced in the 39,XY*O hippocampus. None of the confirmed gene expression changes could be recapitulated by COUMATE administration. We detected ten free, and two sulphated steroids in 40,XY and 39,XY*O brain; surprisingly, the concentrations of all of these were equivalent between groups.

Conclusions
Our data demonstrate that the mutation in 39,XY*O mice: i) directly disrupts expression of the adjacent Erdr1 gene, ii) induces a remarkably limited suite of downstream gene expression changes developmentally, with several of relevance to associated neurobehavioural phenotypes and iii) does not elicit large changes in brain steroid biochemistry. It is possible that individuals with STS/ASMT deficiency exhibit a similarly specific pattern of gene expression changes to the 39,XY*O mouse, and that these contribute towards their abnormal neurobiology. Future work may focus on whether complement pathway function, mitochondrial metabolism and cholesterol biosynthesis pathways are perturbed in such subjects.

Citation

Trent, S., Fry, J. P., Ojarikre, O. A., & Davies, W. (2014). Altered brain gene expression but not steroid biochemistry in a genetic mouse model of neurodevelopmental disorder. Molecular Autism, 5, Article 21. https://doi.org/10.1186/2040-2392-5-21

• Journal Article Type: Article
• Acceptance Date: Feb 19, 2014
• Publication Date: Mar 6, 2014
• Journal: Molecular Autism
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 5
• Article Number: 21
• DOI: https://doi.org/10.1186/2040-2392-5-21
• Keywords: Acetylserotonin O-methyltransferase, COUMATE, Steroid sulphatase, 39,XY*O
• Publisher URL: https://doi.org/10.1186/2040-2392-5-21