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Variants of the SH3 and multiple ankyrin repeat domain 3 ( SHANK3 ) gene, encoding excitatory postsynaptic core scaffolding proteins, are causally associated with numerous neurodevelopmental and neuropsychiatric disorders, including autism spectrum disorder (ASD), bipolar disorder, intellectual disability, and schizophrenia (SCZ). Although detailed synaptic changes of various  Shank3  mutant mice have been well characterized, broader downstream molecular changes, including direct and indirect changes, remain largely unknown. To address this issue, we performed a transcriptome analysis of the medial prefrontal cortex (mPFC) of adult  Shank3 -overexpressing transgenic (TG) mice, using an RNA-sequencing approach. We also re-analyzed previously reported RNA-sequencing results of the striatum of adult  Shank3  TG mice and of the prefrontal cortex of juvenile  Shank3 +/   Δ   C   mice with a 50–70% reduction of Shank3 proteins. We found that several myelin-related genes were significantly downregulated specifically in the mPFC, but not in the striatum or hippocampus, of adult  Shank3  TG mice by comparing the differentially expressed genes (DEGs) of the analyses side by side. Moreover, we also found nine common DEGs between the mPFC and striatum of  Shank3  TG mice, among which we further characterized ASD- and SCZ-associated G protein-coupled receptor 85 ( Gpr85 ), encoding an orphan  Gpr  interacting with PSD-95. Unlike the mPFC-specific decrease of myelin-related genes, we found that the mRNA levels of  Gpr85  increased in multiple brain regions of adult  Shank3  TG mice, whereas the mRNA levels of its family members,  Gpr27  and  Gpr173 , decreased in the cortex and striatum. Intriguingly, in cultured neurons, the mRNA levels of  Gpr27 ,  Gpr85 , and  Gpr173  were modulated by the neuronal activity. Furthermore, exogenously expressed GPR85 was co-localized with PSD-95 and Shank3 in cultured neurons and negatively regulated the number of excitatory synapses, suggesting its potential role in homeostatic regulation of excitatory synapses in  Shank3  TG neurons. Finally, we performed a gene set enrichment analysis of the RNA-sequencing results, which suggested that Shank3 could affect the directional expression pattern of numerous ribosome-related genes in a dosage-dependent manner. To sum up, these results reveal previously unidentified brain region-specific and broad molecular changes in  Shank3 -overexpressing mice, further elucidating the complexity of the molecular pathophysiology of  SHANK3 -associated brain disorders.

Integrative Brain Transcriptome Analysis Reveals Region-Specific and Broad Molecular Changes in Shank3-Overexpressing Mice