Role of the STING→IRF3 Pathway in Ambient GABA Homeostasis and Cognitive Function
Chiranjivi Neupane1,2, Ramesh Sharma1,2, Fei Fei Gao2
1Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08823, Korea.
Summary
The stimulator of interferon genes (STING) pathway upregulates GABA transporters (GATs), causing cognitive dysfunction. Inhibiting STING restores cognitive function by normalizing GABAergic signaling, revealing a new therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- GABA transporters (GATs) are crucial for regulating neurotransmission.
- Altered GATs are implicated in age-related cognitive impairments.
- Transcriptional regulation mechanisms of GATs remain largely unknown.
Purpose of the Study:
- To investigate the role of the STING signaling pathway in regulating GAT expression.
- To elucidate the impact of STING-mediated GAT regulation on cognitive function.
- To identify novel therapeutic targets for cognitive deficits.
Main Methods:
- Utilized genetic and pharmacological STING intervention in mouse models.
- Assessed GAT1 and GAT3 expression levels in the brain.
- Measured ambient GABA concentration and tonic GABAergic inhibition.
- Evaluated spatial learning and working memory performance.
Main Results:
- STING was found to upregulate GAT1 and GAT3 expression, leading to cognitive dysfunction.
- STING inhibition suppressed GAT expression, increased ambient GABA, and enhanced tonic inhibition.
- Cognitive deficits were observed in a type I interferon-independent manner.
- Stimulating the STING→GAT pathway restored cognitive function in STING-deficient mice.
Conclusions:
- The STING signaling pathway regulates GAT expression in a cell-autonomous manner.
- STING represents a novel therapeutic target for addressing GABAergic cognitive deficits.
- Understanding the STING-GAT pathway offers new avenues for treating age-related cognitive impairments.
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