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A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates
Alexander K Hafez1, Amber J Zimmerman2, Grigorios Papageorgiou2
1Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA; Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Cell Reports
|January 19, 2022
Summary
Circular RNAs (circRNAs) like circHomer1 are crucial for brain function. This study reveals circHomer1
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Circular RNAs (circRNAs) are abundant in the brain, but their roles in brain function and psychiatric disorders remain unclear.
- The specific functions of circHomer1 and its relationship with the HOMER1B mRNA isoform in the brain are not well understood.
Purpose of the Study:
- To investigate the role of circHomer1 in brain function and its association with psychiatric disorders.
- To elucidate the molecular mechanisms underlying circHomer1's regulation of Homer1b mRNA and its impact on neuronal function and behavior.
Main Methods:
- Analysis of circHomer1 and HOMER1B mRNA levels in the orbitofrontal cortex (OFC) and neuronal cultures from individuals with psychiatric disorders.
- In vivo knockdown (KD) of circHomer1 and Homer1b in the OFC of animal models.
- RNA immunoprecipitation assays to confirm direct binding between circHomer1 and Homer1b mRNA.
- Behavioral assessments, including chance reversal learning, to evaluate functional consequences.
Main Results:
- circHomer1 levels are inversely associated with HOMER1B mRNA isoform levels in the OFC and neuronal cultures of subjects with psychiatric disorders.
- In vivo circHomer1 KD in the OFC inhibits synaptic Homer1b mRNA expression.
- circHomer1 directly binds to Homer1b mRNA; Homer1b KD enhances synaptic circHomer1 and improves behavioral flexibility.
- Double KD of circHomer1 and Homer1b rescues circHomer1-associated deficits in learning and synaptic gene expression.
Conclusions:
- circHomer1 plays a critical role in regulating synaptic Homer1b mRNA expression and influencing behavioral flexibility.
- The interaction between circHomer1 and Homer1b mRNA is a key mechanism in brain function and psychiatric disorders.
- These findings provide novel insights into the function of circRNAs in the central nervous system and their potential as therapeutic targets.
