Activation Of GABA_B Receptor Upregulates Expression Of FMRP In Neurons

Fragile X mental retardation protein(FMRP) is a RNA-binding protein, able to regulate RNA transcription and relative gene expression in advance. The dysregulation of FMRP expression is the main reason account for Fragile X Syndrome, which appears on the FXS patients are autistic relative behaviors, social avoidance, seizure syndrome, sleep disorders, hyperactivity and etc. ?-amino butyric acid(GABA) is the main inhibitory neurotransmitter in the central nervous system, the metabotropic ?-amino butyric acid type B receptor(GABABR) is reported to play an important role in multiple neurologic diseases such as seizures. It is reported that agonist of GABABR, baclofen, could rescue FXS-relative phenotype deficits in Fmr1 knock out mice, such as reducing audiogenic seizure, normalized spine density, regular protein synthesis, internalization of AMPA receptor. However, the signal pathway between GABABR and FMRP expression regulation is still unclear. This article aims to show that the GABABR activation-induced phosphorylation of cAMP response element binding protein(CREB), upregulates FMRP expression. Further, the upregulation of FMRP is realized by transactivation from GABABR to insulin-like growth factor-1 receptor(IGF1-R). Finally, a positive allosteric modulator(PAM) of GABABR, CGP7930, is also able to increase FMRP expression in cerebellum granular neurons(CGNs). In conclusion, GABABR plays certain role in the regulation of FMRP, which enables GABABR as potential target for research and development of medicine aiming to FXS.