GABA B receptor upregulates fragile X mental retardation protein expression in neurons

Abstract

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. Î 3-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.