Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations
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Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations. / Gordon, Aaron; Forsingdal, Annika; Klewe, Ib Vestergaard; Nielsen, Jacob; Didriksen, Michael; Werge, Thomas; Geschwind, Daniel H.
In: Molecular Psychiatry, Vol. 26, 2021, p. 1520–1534.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations
AU - Gordon, Aaron
AU - Forsingdal, Annika
AU - Klewe, Ib Vestergaard
AU - Nielsen, Jacob
AU - Didriksen, Michael
AU - Werge, Thomas
AU - Geschwind, Daniel H.
PY - 2021
Y1 - 2021
N2 - 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 postmortem factors are 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 cortical and two hippocampal modules of co-expressed genes that were dysregulated across all three mouse models. One cortical module was associated with neuronal energetics and firing rate, and overlapped with changes identified in postmortem 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 changes in neuronal energetics and neuropsychiatric disorders in humans.
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 postmortem factors are 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 cortical and two hippocampal modules of co-expressed genes that were dysregulated across all three mouse models. One cortical module was associated with neuronal energetics and firing rate, and overlapped with changes identified in postmortem 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 changes in neuronal energetics and neuropsychiatric disorders in humans.
U2 - 10.1038/s41380-019-0576-0
DO - 10.1038/s41380-019-0576-0
M3 - Journal article
C2 - 31705054
AN - SCOPUS:85075013852
VL - 26
SP - 1520
EP - 1534
JO - Molecular Psychiatry
JF - Molecular Psychiatry
SN - 1359-4184
ER -
ID: 238483870