CircSATB2 modulates fear extinction memory via Robo3-driven synaptic plasticity.

Circular RNAs (circRNAs) are novel class of stable regulatory RNAs abundantly expressed in the brain. However, their role in fear extinction (EXT) memory remains largely unexplored. To investigate the mechanisms of Circular Special AT-rich Sequence Binding Protein 2 (circSatb2) in EXT memory, we constructed a lentivirus overexpressing circSatb2 and injected it into the infralimbic prefrontal cortex (ILPFC) of the mouse brain. Following extinction training and subsequent testing, we observed an essential role of circSatb2 in this dynamic process. RNA sequencing (RNA-seq) and bioinformatics analyses revealed that circSatb2 enhances the transcription of Roundabout Guidance Receptor 3 (Robo3), a key gene implicated in axon guidance and synaptic plasticity, which was validated by RT-qPCR. Neuronal morphology was assessed using confocal microscopy to determine changes in dendritic spine density. Our results demonstrated that circSatb2 significantly enhances Robo3 transcription, leading to increased dendritic spine formation and improved synaptic plasticity. In conclusion, circSatb2 promotes the formation of EXT memory by upregulating Robo3 transcription and enhancing synaptic plasticity. These findings position circSatb2 as a potential therapeutic target for disorders associated with memory impairment.