Social Encounters Reveal Brain Region-Specific Gene Expression Changes in Shank3 Null Mice
Objectives: The goal of the present study was to examine the transcriptional response to a social stimulus in specific brain regions.
Methods: Adult male mice with a deletion in exons 13-16 of the Shank3 gene, or their wildtype littermates, were exposed to a social or non-social stimulus for 30 minutes. Ten hours later, tissue was extracted from the prefrontal cortex, medial amygdala and lateral amygdala for RNA sequencing analysis (Illumina HiSeq 2000). Count-based differential expression analysis was performed (edgeR_3.4.2) for the following comparisons: 1) mutant vs wildtype in nonsocial condition, 2) mutant vs wildtype in social condition, 3) social vs nonsocial in wildtype, 4) social vs nonsocial in mutant, and 5) the interaction across genotypes and conditions. Analyses of the differentially expressed genes in each comparison (p<0.05) were performed using WebGestalt for Gene Ontology, KEGG, and Wikipathway analyses, and using Ingenuity Pathway Analysis for Canonical Pathway, Disease and Function, and Network analyses. Differentially expressed genes were also compared to genes implicated in ASD, as collected in the SFARI Genes database.
Results: Genes implicated in ASD were significantly enriched among differentially expressed genes in all brain regions, particularly in the mutant versus wildtype comparisons in the non-social condition (p≤0.0001), as well as in the interaction analysis across genotypes and conditions (p<0.03). Pathway analyses revealed that genes involved in neuronal signaling and development were differentially expressed in nearly all comparisons, across all brain regions examined. Genes relevant for behavior, developmental and neurological disorders were also enriched. The axonal guidance signaling pathway was one of the most consistently significant canonical pathways identified as having enriched gene networks, particularly in mutant vs wildtype comparisons (p ranging from 0.00359 to <0.0001).
Conclusions: These findings indicate that the Shank3 null mouse model has changes in gene expression relevant to ASD, indicated by the prevalence of autism-associated genes, as well as the consistent enrichment of pathways relevant for neuronal signaling and development. Future studies may elucidate the role of specific networks in the social deficits observed in Shank3 null mice.
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