The circular RNA circmglur5b modulates symptoms of fragile X syndrome
Fragile X syndrome (FXS) is the most frequent inherited neurodevelopmental disorder and a leading genetic cause of autism spectrum disorder (ASD). It is characterized by hyperactivity, epileptic seizures, and autistic traits. FXS patients lack the fragile X mental retardation protein (FMRP) due to the transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. Loss of FMRP alters axonal transport and mRNA translation, as well as synaptic structure and function, thereby affecting neurodevelopment and behavior. In a zebrafish model of FXS (fmr1-/-), we demonstrated interactions between FMRP and RNA-editing adenosine deaminase acting on RNA (ADAR) enzyme, increased axonal branching and synaptic density, along with hyper-locomotor activity. ADAR regulates the formation of circular RNAs (circRNAs), which are generated by the back-splicing of exons and introns, stable and enriched in synapses. Here, RNA-seq data from fmr1-/- synaptosomes revealed differentially expressed circRNAs. Specifically, levels of circmglur5b, a maternally inherited circRNA, were markedly elevated in fmr1-/- embryos, larvae and adults, while linear mglur5b mRNA levels did not change. Overexpressing circmglur5b in wild-type (fmr1+/+) larvae recapitulates fmr1-/- zebrafish phenotypes, including increased synaptic density, hyper-locomotor activity, sleep disturbances, and impaired social preference. These findings show that the loss of FMRP increases circmglur5b expression, which modulates synaptic overgrowth and behavioral deficits, suggesting circmglur5b as a regulator and biomarker in FXS.