Social isolation-induced transcriptomic changes in mouse hippocampus impact the synapse and show convergence with human genetic risk for neurodevelopmental phenotypes

Abstract

Early life stress (ELS) can impact brain development and is a risk factor for neurodevelopmental disorders such as schizophrenia. Post-weaning social isolation (SI) is used to model ELS in animals, using isolation stress to disrupt a normal developmental trajectory. We aimed to investigate how SI affects the expression of genes in mouse hippocampus and to investigate how these changes related to the genetic basis of neurodevelopmental phenotypes. BL/6J mice were exposed to post-weaning SI (PD21-25) or treated as group-housed controls (n = 7-8 per group). RNA sequencing was performed on tissue samples from the hippocampus of adult male and female mice. Four hundred and 1,215 differentially-expressed genes (DEGs) at a false discovery rate of < 0.05 were detected between SI and control samples for males and females respectively. DEGS for both males and females were significantly overrepresented in gene ontologies related to synaptic structure and function, especially the post-synapse. DEGs were enriched for common variant (SNP) heritability in humans that contributes to risk of neuropsychiatric disorders (schizophrenia, bipolar disorder) and to cognitive function. DEGs were also enriched for genes harbouring rare de novo variants that contribute to autism spectrum disorder and other developmental disorders. Finally, cell type analysis revealed populations of hippocampal astrocytes that were enriched for DEGs, indicating effects in these cell types as well as neurons. Overall, these data suggest a convergence between genes dysregulated by the SI stressor in the mouse and genes associated with neurodevelopmental disorders and cognitive phenotypes in humans. Author SummaryEarly life stress increases risk of developing neuropsychiatric and neurodevelopmental disorders. Early life stress can be modelled in animals using social isolation (SI) where animals are separated from others after they have stopped weaning and are housed individually rather than in groups. Here, we investigated the effect of SI on gene expression in the hippocampus, a brain region that regulates stress response and emotion, and how this relates to the known genetic aetiology of neuropsychiatric disorders and traits such as cognitive function. We found that genes altered by SI play a role in how synapses form and function - these are the connection points between nerve cells in the brain. We also found these altered genes are also the genes where common changes in the DNA code can increase risk for schizophrenia, bipolar disorder and influence cognitive ability, and where rare changes in the DNA code increase risk for autism spectrum disorder and developmental disorder. Finally, these genes altered by SI are also highly expressed in astrocytes, cells that help nerve cells to function in the hippocampus. Overall, these data suggest a convergence between genes affected by SI, the environmental stressor, and the genes associated with neurodevelopmental disorders and cognition.