Isoform switching of steroid receptor co-activator-1 attenuates glucocorticoid-induced anxiogenic amygdala CRH...

Area of Science:

• Neuroscience
• Molecular Biology
• Endocrinology

Background:

• Maladaptive glucocorticoid effects are implicated in stress-related psychopathology.
• The glucocorticoid receptor (GR) mediates these effects through various signaling pathways.
• Corticotropin releasing hormone (CRH) is a key mediator in stress responses.

Purpose of the Study:

• To test if manipulating coregulators can mitigate maladaptive GR effects on fear behavior.
• To investigate the role of steroid receptor coactivator-1 (SRC-1) splice variants in GR signaling.
• To determine if altering SRC-1 splicing affects CRH gene expression and methylation.

Main Methods:

• Antisense-mediated exon-skipping was used to alter SRC-1 splice variants in the mouse central amygdala.
• CRH mRNA expression and promoter methylation were analyzed.
• Glucocorticoid responsiveness of the Fkbp5 gene was assessed.
• Glucocorticoid-dependent exploratory behavior and fear memory consolidation were evaluated.

Main Results:

• Shifting SRC-1 splicing towards the repressive SRC-1a isoform reduced glucocorticoid-induced CRH mRNA expression.
• Increased methylation of the Crh promoter was observed.
• The Fkbp5 gene remained responsive to glucocorticoids, showing gene-specific effects.
• Altered SRC-1 splicing affected exploratory behavior and attenuated fear memory consolidation.

Conclusions:

• Manipulation of GR signaling pathways, specifically targeting the CRH gene, can selectively reduce maladaptive glucocorticoid effects.
• Altering the ratio of SRC-1 splice variants offers a potential strategy to modulate stress responses.
• These findings highlight the role of coregulators in fine-tuning GR actions and their implications for psychopathology.