Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and...

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Genetic risk for psychiatric disorders like schizophrenia and autism spectrum disorder (ASD) is complex.
• Identifying shared molecular pathways is crucial for understanding how distinct genetic risks converge.
• Previous studies suggest shared pathways but lack clarity on specific genetic factors and confounding influences.

Purpose of the Study:

• To investigate shared molecular pathways in mouse models with genetic risk factors for schizophrenia and ASD.
• To determine if specific copy number variants (CNVs) associated with these disorders lead to convergent gene expression changes.
• To link molecular alterations in mouse models to findings in human postmortem brain tissue.

Main Methods:

• Transcriptome analysis of the cortex and hippocampus in three mouse lines modeling human CNVs (15q13.3, 22q11.2, and 1q21.1 deletions).
• Gene network analysis to identify modules of co-expressed genes dysregulated across models.
• Comparison of findings with gene expression changes in postmortem human brain from schizophrenia (SCZ) and ASD patients.

Main Results:

• Little overlap in differential gene expression at the individual gene level across the three mouse models.
• Gene network analysis revealed two dysregulated cortical and two hippocampal modules common to all three models.
• One cortical module implicated neuronal energetics and firing rate, showing overlap with human postmortem brain findings in SCZ and ASD.

Conclusions:

• Mouse models with major risk alleles for schizophrenia and ASD exhibit convergent gene expression patterns.
• These findings highlight the role of neuronal energetics as a shared molecular pathway in neuropsychiatric disorders.
• The study strengthens the connection between genetic risk, neuronal energetics, and complex brain conditions in humans.