The role of the circular RNA circmGluR5b in the development and treatment of fragile X syndrome
2Department of biochemistry, The Weizmann Institute of Science
Fragile-X syndrome (FXS) is the most frequent inherited neurodevelopmental disorder causing mental retardation. FXS patients lack fragile-X mental retardation protein (Fmrp) due to transcriptional silencing of the fragile-X mental retardation 1 (fmr1) gene.
The transparent zebrafish fmr1 mutant (fmr1-/-) is an attractive model to study the mechanisms and treatment of FXS. We used RNA-seq of synaptosomes to profile the expression of circular RNAs (circRNAs) in the brain of fmr1-/- fish. CircRNAs are enriched in synapses, but their role in regulating synaptic activity and behavior is unclear. We postulate that loss of Fmrp alters circRNA expression, trafficking, and function, particularly in synapses, which affect neuronal circuit formation and behavior in fmr1-/- zebrafish. Strengthening this hypothesis, our RNA-seq data of the fmr1-/- synaptosomes showed that the expression of circmGluR5b was markedly increased in fmr1-/- brains. CircmGluR5b is derived from the synaptic gene mGluR5b, which encodes metabotropic glutamate receptor 5b protein. Notably, metabotropic glutamate receptor signaling is elevated in human FXS patients.
We aim to understand the role of circmGluR5b in regulating the neurological and behavioral symptoms of FXS. To do so, we generated transgenic circmGluR5b overexpressing fish. We used two-photon imaging to monitor neuronal activity, neurite growth, and structural synaptic plasticity, and high-throughput video tracking systems to study the effect of circmGluR5b on locomotor activity, arousal, and sleep.
Our exiting findings suggest that circmGluR5b has a significant role in the development of FXS, making it a valuable potential therapeutic target.