Format

Send to

Choose Destination
Mol Psychiatry. 2019 Nov 8. doi: 10.1038/s41380-019-0576-0. [Epub ahead of print]

Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations.

Author information

1
Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
2
Division of Synaptic Transmission, H. Lundbeck A/S, Valby, Denmark.
3
Institute of Biological Psychiatry, Mental Health Services Capital Region of Denmark, Copenhagen, Denmark.
4
Institute of Biological Psychiatry, Mental Health Services Capital Region of Denmark, Copenhagen, Denmark. thomas.werge@regionh.dk.
5
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark. thomas.werge@regionh.dk.
6
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. thomas.werge@regionh.dk.
7
Lundbeck Foundation GeoGenetics Centre, Natural History Museum of Denmark, University of Copenhagen, 1350, Copenhagen, Denmark. thomas.werge@regionh.dk.
8
Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA. dhg@mednet.ucla.edu.
9
Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. dhg@mednet.ucla.edu.
10
Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. dhg@mednet.ucla.edu.
11
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. dhg@mednet.ucla.edu.

Abstract

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.

PMID:
31705054
DOI:
10.1038/s41380-019-0576-0

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center