GABAB receptor upregulates fragile X mental retardation protein expression in neurons

Fragile X mental retardation protein (FMRP) is an RNA-binding protein important for the control of translation and synaptic function. The mutation or silencing of FMRP causes Fragile X syndrome (FXS), which leads to intellectual disability and social impairment. gamma-aminobutyric acid ( GABA) is the major inhibitory neurotransmitter of the mammalian central nervous system, and its metabotropic GABA(B) receptor has been implicated in various mental disorders. The GABA(B) receptor agonist baclofen has been shown to improve FXS symptoms in a mouse model and in human patients, but the signaling events linking the GABA(B) receptor and FMRP are unknown. In this study, we found that GABA(B) receptor activation upregulated cAMP response element binding protein-dependent Fmrp expression in cultured mouse cerebellar granule neurons via two distinct mechanisms: the transactivation of insulin-like growth factor-1 receptor and activation of protein kinase C. In addition, a positive allosteric modulator of the GABA(B) receptor, CGP7930, stimulated Fmrp expression in neurons. These results suggest a role for GABA(B) receptor in Fmrp regulation and a potential interest of GABA(B) receptor signaling in FXS improvement.