Sex differences in protein expression in the mouse brain and their perturbations in a model of Down syndrome

Abstract

BackgroundWhile many sex differences in structure and function of the mammalian brain have been described, the molecular correlates of these differences are not broadly known. Also unknown is how sex differences at the protein level are perturbed by mutations that lead to intellectual disability (ID). Down syndrome (DS) is the most common genetic cause of ID and is due to trisomy of human chromosome 21 (Hsa21) and the resulting increased expression of Hsa21-encoded genes. The Dp(10)1Yey mouse model (Dp10) of DS is trisomic for orthologs of 39 Hsa21 protein-coding genes that map to mouse chromosome 10 (Mmu10), including four genes with known sex differences in functional properties. How these genes contribute to the DS cognitive phenotype is not known.MethodsUsing reverse phase protein arrays, levels of ~100 proteins/protein modifications were measured in the hippocampus, cerebellum, and cortex of female and male controls and their trisomic Dp10 littermates. Proteins were chosen for their known roles in learning/memory and synaptic plasticity and include components of the MAPK, MTOR, and apoptosis pathways, immediate early genes, and subunits of ionotropic glutamate receptors. Protein levels were compared between genotypes, sexes, and brain regions using a three-level mixed effects model and the Benjamini-Hochberg correction for multiple testing.ResultsIn control mice, levels of approximately one half of the proteins differ significantly between females and males in at least one brain region; in the hippocampus alone, levels of 40 % of the proteins are significantly higher in females. Trisomy of the Mmu10 segment differentially affects female and male profiles, perturbing protein levels most in the cerebellum of female Dp10 and most in the hippocampus of male Dp10. Cortex is minimally affected by sex and genotype. Diverse pathways and processes are implicated in both sex and genotype differences.ConclusionsThe extensive sex differences in control mice in levels of proteins involved in learning/memory illustrate the molecular complexity underlying sex differences in normal neurological processes. The sex-specific abnormalities in the Dp10 suggest the possibility of sex-specific phenotypic features in DS and reinforce the need to use female as well as male mice, in particular in preclinical evaluations of drug responses.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-015-0043-9) contains supplementary material, which is available to authorized users.

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“…Likewise, also in a recent study of postmortem human brains from men and women only subtle gene expression differences were detected [61]. Small expression differences between the sexes were also confirmed on the protein level in a recent study of approximately 100 proteins in several brain regions [41] showing that only 2 of the 51 sexually dimorphic proteins differed by >30%. As previously suggested [60], this may indicate that differences between the sexes in brain function and behavior may arise from combinatorial effects of a large number of proteins.…”

“…In contrast to mRNA-based expression analysis, proteomics has the advantage of studying proteins—the functional molecules of the cell [40]. Still, few studies have been performed concerning sex differences in protein expression on large or proteome-wide scale of the mammalian brain [41–44]. …”

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“…[30][31][32][33] Dr. Akil also discussed the importance of studying sex differences in brain function and critical brain development in the context of SUD. [35][36][37][38][39] 34 Allelic variations that increase the susceptibility to OUD may differ between men and women when considering the vast differences in gene expression that are observed between sexes in various brain diseases in both human and animal studies.…”