Cellular and Molecular Neurobiology
Author: Lucía Szychowski | Email: luszychowski@gmail.com
Lucía Szychowski1°, Camila Pannunzio1°,Sebastián Alejandro Giusti1°, Damián Refojo1°
1° Instituto de Biomedicina de Buenos Aires (IBioBA)
Circular RNAs (circRNAs) are single-stranded, covalently-closed non-coding RNAs that contain exonic sequences from protein-coding genes and are formed by backsplicing, a mechanism in which a donor site splices with an upstream acceptor site. Despite thousands of identified circRNAs, their biological roles remain mostly unexplored.
We previously identified many circRNAs with higher expression levels than their linear isoforms in human and mouse central nervous systems. For functional characterization, we focused on circTulp4, derived from the Tulp4 gene, due to its high enrichment in the brain. To study its function, we created a circTulp4-deficient (CD) mouse model where circTulp4 is downregulated without affecting linear RNA or protein levels.
CircTulp4 was found to regulate excitatory neurotransmission in male mice, and its loss led to increased locomotion, stress sensitivity, and altered reward-related behavior, suggesting a dopaminergic pathway alteration. Testing amphetamine-induced locomotion, CD mice showed a heightened response, suggesting circTulp4’s role in dopaminergic circuits involved in locomotion. CD females also showed increased shock sensitivity in a passive avoidance test, hinting at potential memory effects. We also used RT-qPCR to assess circTulp4 and dopaminergic component levels in various brain regions.
This study demonstrates circTulp4’s significant influence on behavior and neuronal function, focusing on its role in the dopaminergic pathway.