The Potential Involvement of the Y-Chromosome Gene, SRY, in Attention-Deficit Hyperactivity Disorder (ADHD)

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, characterised by symptoms of inattention and/or hyperactivity. Although the aetiology of ADHD remains uncertain males are diagnosed at a ratio of 3 to 1 compared to females. Recent studies indicate that the Y-chromosome gene, SRY, may contribute to disparities between sexes in ADHD. Previous work from my laboratory demonstrates that SRY is expressed in the male that are linked to symptoms of ADHD, such as the prefrontal cortex, hippocampus and striatum and that SRY regulates genes involved in ADHD symptoms, such as dopamine and GABA pathway genes, exclusively in males. Moreover, preliminary results from my laboratory show that SRY expression is down-regulated in the prefrontal cortex, hippocampus and striatum in the spontaneous-hypertensive rat (SHR) model of ADHD. In view of these results, I hypothesise that Reduction of brain Sry expression contributes to the dysregulation of dopamine and GABA transmission, and consequently symptoms in male ADHD. To test the hypothesis, I assessed the effect of reducing brain Sry expression - via intracerebral antisense oligonucleotide (ASO) infusion - on dopamine and GABA pathway gene and protein expression in male Wistar-Kyoto (WKY) rats or male SHRs. qPCR analysis revealed that ASO infusion led to significant reductions in Sry mRNA expression in the striatum and hippocampus of male WKYs, which were paralleled by reductions in D2r, Gad1, and Ki67 mRNA expression. Similarly, Sry, D2r, Gad1, and Ki67 mRNA expression were reduced in the striatum and hippocampus of male SHRs when compared to male WKYs. Co-immunofluorescence studies revealed similar reductions in Sry protein expression in the striatum and hippocampus following ASO infusion in male WKY rats or male SHRs. These results indicate that Sry dysregulation may impact neurotransmitter signalling and cellular proliferation in the male brain, which are known to be disrupted in ADHD. Developing interventions that target Sry may represent a novel sex-specific therapeutic strategy for ADHD.