Abstract
BackgroundThe 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.MethodsUsing 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.ResultsMicroarray 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.ConclusionsOur 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.
Highlights
The 39,XY*O mouse, which lacks the orthologues of the Attention Deficit Hyperactivity Disorder (ADHD) and autism candidate genes steroid sulphatase (STS) and ASMT, exhibits behavioural phenotypes relevant to developmental disorders
A further 1,536 transcripts were potentially more subtly differentially expressed; of these, 47 had previously been implicated in autism and/ or ADHD according to relevant online databases [28,29,30]: Abat, Arhgap15, Cdh8, Chrna7, Cldn5, Cntn3, Crygc, Cttnbp2, Ctnna2, Dctn5, Dhcr7, Dhrs3, Ehmt1, Elovl6, Eif4e1b, Eln, Fbxo40, Gclc, Gdi1, Gfod1, Gpd2, Grid2, Hepacam, Hes1, Hes6, Irak1, Kcnj10, Lphn3, Lrp2, Lrrn3, Mcph1, Mctp1, Mid1, Nlgn1, Npy5r, Nucb1, Park2, Pdzd4, Plcb1, Prodh, Prrt2, Prune2, Scn2a1, Slc25a12, Srsf3, Syngap1 and Ythdc2
The expression of only seven of the 13 genes was confirmed as being significantly different between the two experimental groups by Quantitative PCR (qPCR) (Figure 1A): six upregulated: Vmn2r86: t8.00 = −6.11, P < 0.001, Sfi1: t16 = −8.62, P < 0.001, Pisd-ps1: t11.84 = −1.84, P < 0.05, Tagap1: t17 = −3.32, P < 0.005, C1qc: t9.07 = −11.47, P < 0.001, Metap1d: t9.29 = −12.02, P < 0.001
Summary
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. Autism spectrum disorders (ASDs) and Attention Deficit Hyperactivity Disorder (ADHD) exhibit partially overlapping neurobehavioural symptoms, frequent comorbidity, altered monoaminergic function, and shared genetic aetiology [1] Both types of disorder are significantly more frequently diagnosed in males than in females, suggesting a potential role for sex-linked genetic risk variants [2], and both can have long-term adverse consequences for example, increased risk for alcohol dependence in ADHD [3] or lack of independence, close social ties and employment in ASDs [4]. As sulphated and non-sulphated steroid hormones can act as modulators at key neurotransmitter receptors, including N-methyl-D-aspartic acid (NMDA) and γ-aminobutyric acid type A (GABAA) receptors [9], lack of STS developmentally could potentially elicit important effects on neuronal organisation processes mediated by these neurotransmitters [10]
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