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Genetic variants of the SH3 and multiple ankyrin repeat domains 3 ( SHANK3 ) gene, which encodes excitatory postsynaptic core scaffolds cause numerous brain disorders. Several lines of  Shank3  knock-out (KO) mice with deletions of different  Shank3  exons have previously been generated and characterized. The different  Shank3  KO mouse lines have both common and line-specific phenotypes. Shank3 isoform diversity is considered a mechanism underlying phenotypic heterogeneity, and compensatory changes through regulation of  Shank3  expression may contribute to this heterogeneity. However, whether such compensatory changes occur in  Shank3  KO mouse lines has not been investigated in detail. Using previously reported RNA-sequencing analyses, we identified an unexpected increase in  Shank3  transcripts in two different  Shank3  mutant mouse lines ( Shank3B  and  Shank3ΔC ) having partial deletions of  Shank3  exons. We validated an increase in  Shank3  transcripts in the hippocampus, cortex, and striatum, but not in the cerebellum, of  Shank3B  heterozygous (HET) and KO mice, using qRT-PCR analyses. In particular, expression of the N-terminal exons 1–12, but not the more C-terminal exons 19–22, was observed to increase in  Shank3B  mice with deletion of exons 13–16. This suggests a selective compensatory activation of upstream  Shank3  promoters. Furthermore, using domain-specific Shank3 antibodies, we confirmed that the increased  Shank3  transcripts in  Shank3B  KO mice produced a small Shank3 isoform that was not detected in wild-type mice. Taken together, our results illustrate another layer of complexity in the regulation of  Shank3  expression in the brain, which may also contribute to the phenotypic heterogeneity of different  Shank3  KO mouse lines.

Unexpected Compensatory Increase in Shank3 Transcripts in Shank3 Knock-Out Mice Having Partial Deletions of Exons