Key result
Chronic social defeat stress induced modest and dynamic regulation of A-to-I RNA editing within numerous transcripts in the mPFC and BLA of mice, including the Htr2c transcript in susceptible mice.
Why the study?
Only a small fraction of recoding sites has been investigated in the brain following stress, leaving the role of RNA editing in transcriptome regulation after environmental stimuli poorly understood.
Chronic social defeat stress induces dynamic A-to-I RNA editing in the mouse brain, highlighting a potential molecular mechanism for stress susceptibility and resilience.
Answers are grounded in this paper and cite their sources.
Stress-induced editing changes in mice are hypothesis-generating; leaves open a mechanistic role in human psychiatric vulnerability.
Adenosine to inosine (A-to-I) RNA editing is a co/post-transcriptional modification of double stranded RNA, catalysed by the adenosine deaminase acting on RNA (ADAR) family of enzymes, which results in recognition of inosine as guanosine by translational and splicing machinery causing potential recoding events in amino acid sequences. A-to-I editing is prominent within brain-specific transcripts and dysregulation of editing at several well-studied loci (e.g., Gria2, Htr2c) has been implicated in acute and chronic stress in rodents as well as neurological (e.g., Alzheimer’s) and psychopathological disorders such as schizophrenia and major depressive disorder. However, only a small fraction of recoding sites has been investigated within the brain following stress and our understanding of the role of RNA editing in transcriptome regulation following environmental stimuli remains poorly understood. Thus, we aimed to investigate A-to-I editing at hundreds of loci following chronic social defeat stress (CSDS) in mice within cortico-limbic regions responsive to chronic stress regulation. Adult male mice were subjected to CSDS or control conditions for 21 days and dynamic regulation of A-to-I editing was investigated 2 and 8 days following the final defeat within both the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). Employing a targeted resequencing approach, which utilises microfluidics-based multiplex PCR coupled with next-generation sequencing, we analysed A-to-I editing at ~100 high confidence editing sites within the mouse brain. CSDS resulted in acute regulation of transcripts encoding several ADAR enzymes, which normalised 8 days following the final defeat and was specific for susceptible mice. In contrast, sequencing analysis revealed modest and dynamic regulation of A-to-I editing within numerous transcripts in both the mPFC and BLA of resilient and susceptible mice at both 2 and 8 days following CSDS with minimal overlap between regions and time points. Editing within the Htr2c transcript and relative abundance of Htr2c mRNA variants was also observed within the BLA of susceptible mice 2 days following CSDS. These results indicate dynamic RNA editing within discrete brain regions following CSDS in mice, further implicating A-to-I editing as a stress-sensitive molecular mechanism within the brain of potential relevance to resiliency and susceptibility to CSDS.
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Dick et al. (2019) studied Chronic Social Defeat Stress (n=41). Chronic Social Defeat Stress (CSDS) vs. Daily handling (Control) was evaluated on Global levels of A-to-I RNA editing within the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC). Chronic social defeat stress induced modest and dynamic regulation of A-to-I RNA editing within numerous transcripts in the mPFC and BLA of mice, including the Htr2c transcript in susceptible mice.
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