Sex Hormones Regulate SHANK Expression

Abstract

Autism spectrum disorders (ASD) have a higher prevalence in male individuals compared to females, with a ratio of affected boys compared to girls of 4:1 for ASD and 11:1 for Asperger syndrome. Mutations in the <i>SHANK</i> genes (comprising <i>SHANK1</i>, <i>SHANK2</i> and <i>SHANK3</i>) coding for postsynaptic scaffolding proteins have been tightly associated with ASD. As early brain development is strongly influenced by sex hormones, we investigated the effect of dihydrotestosterone (DHT) and 17β-estradiol on <i>SHANK</i> expression in a human neuroblastoma cell model. Both sex hormones had a significant impact on the expression of all three <i>SHANK</i> genes, which could be effectively blocked by androgen and estrogen receptor antagonists. In neuron-specific androgen receptor knock-out mice (<i>Ar</i> ^NesCre), we found a nominal significant reduction of all <i>Shank</i> genes at postnatal day 7.5 in the cortex. In the developing cortex of wild-type (WT) CD1 mice, a sex-differential protein expression was identified for all Shanks at embryonic day 17.5 and postnatal day 7.5 with significantly higher protein levels in male compared to female mice. Together, we could show that <i>SHANK</i> expression is influenced by sex hormones leading to a sex-differential expression, thus providing novel insights into the sex bias in ASD.