GABAB 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. γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the mammalian central nervous system, and its metabotropic GABAB receptor has been implicated in various mental disorders. The GABAB receptor agonist baclofen has been shown to improve FXS symptoms in a mouse model and in human patients, but the signaling events linking the GABAB receptor and FMRP are unknown. In this study, we found that GABAB 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 GABAB receptor, CGP7930, stimulated Fmrp expression in neurons. These results suggest a role for GABAB receptor in Fmrp regulation and a potential interest of GABAB receptor signaling in FXS improvement.

FRET-Based Sensors Unravel Activation and Allosteric Modulation of the GABAB Receptor

“…The increased precision of our molecular tools allowed us to dissect three different modes of action for the three PAMs tested. We show that CGP7930 and rac-BHFF can act as ago-PAMs, as reported previously for the recombinant and native GABA B receptor (Malherbe et al, 2008;Sun et al, 2016;Zhang et al, 2015). They also potentiate agonist efficacy, while rac-BHFF strongly potentiates both agonist potency and efficacy, and has the strongest effect in potentiating the agonistinduced ECD reorientation.…”

Effects of acute administration of the GABA(B) receptor agonist baclofen on behavioral flexibility in rats

“…In transgenic mice with interneuron deficits, the selective GABA(B) receptor agonist baclofen normalizes pyramidal neuron hyperexcitability and restores gamma synchrony (Billingslea et al 2014; Bortolato et al 2007; Gandal et al 2012; Henderson et al 2012; Qin et al 2015; Silverman et al 2015). Moreover, drugs targeting GABA(B) receptors (including baclofen) enhance several aspects of cognitive function in preclinical animal models, including some that depend on the PFC (Banuelos et al 2014; Beas et al in press; Lasarge et al 2009; Qin et al 2015; Zhang et al 2015). Finally, baclofen has a strong safety profile, as it is used clinically as a treatment for spasticity, and has been explored as a treatment for addiction (Colombo et al 2004; Franklin et al 2009; Garbutt et al 2010; Liu and Wang 2015; Margetis et al 2014; Morley et al 2014).…”

The neurobiology of the Prader-Willi phenotype of fragile X syndrome

“…IGF-1 enhances GABA activity that is deficient in FXS both with and without the PWP (Figure 2)(45). In addition, the GABAB receptor-mediated transactivation of IGF-1 receptors leads to cAMP response elementbinding protein (CREB) activation which in turn binds to FMR1 and increases FMRP levels (46). Therefore, GH in FXS-PWP could stimulate the release of IGF-1 to enhance the GABA system, and increase the residual expression of FMR1 particularly in those who are mosaic or partially unmethylated.…”