RT Journal Article
SR Electronic
T1 Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 625368
DO 10.1101/625368
A1 Gordon, Aaron
A1 Grønborg-Forsingdal, Annika
A1 Klewe, Ib Vestergaard
A1 Nielsen, Jacob
A1 Didriksen, Michael
A1 Werge, Thomas
A1 Geschwind, Daniel
YR 2019
UL http://biorxiv.org/content/early/2019/05/02/625368.abstract
AB Genetic risk for psychiatric illness is complex, so identification of shared molecular pathways where distinct forms of genetic risk might coincide is of substantial interest. A growing body of genetic and genomic studies suggest that such shared molecular pathways exist across disorders with different clinical presentations, such as schizophrenia and autism spectrum disorder (ASD). But how this relates to specific genetic risk factors is unknown. Further, whether some of the molecular changes identified in brain relate to potentially confounding antemortem or post-mortem factors is difficult to prove. We analyzed the transcriptome from the cortex and hippocampus of three mouse lines modeling human copy number variants (CNVs) associated with schizophrenia and ASD: Df(h15q13)/+, Df(h22q11)/+, and Df(h1q21)/+ which carry the 15q13.3 deletion, 22q11.2 deletion, and 1q21.1 deletion, respectively. Although we found very little overlap of differential expression at the level of individual genes, gene network analysis identified two modules of co-expressed genes that were dysregulated across all three mouse models. One module observed in both cortex and hippocampus was associated with neuronal energetics and firing rate, and overlapped with changes identified in post mortem human brain from SCZ and ASD patients. These data highlight aspects of convergent gene expression in mouse models harboring major risk alleles, and strengthen the connection between neuronal energetic dysfunction and neuropsychiatric disorders in humans.