Reversal of Disease-Related Pathologies in the Fragile X Mouse Model by Selective Activation of GABA _B Receptors with Arbaclofen

Abstract

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism, results from the transcriptional silencing of FMR1 and loss of the mRNA translational repressor protein fragile X mental retardation protein (FMRP). Patients with FXS exhibit changes in neuronal dendritic spine morphology, a pathology associated with altered synaptic function. Studies in the mouse model of fragile X have shown that loss of FMRP causes excessive synaptic protein synthesis, which results in synaptic dysfunction and altered spine morphology. We tested whether the pharmacologic activation of the γ-aminobutyric acid type B (GABA(B)) receptor could correct or reverse these phenotypes in Fmr1-knockout mice. Basal protein synthesis, which is elevated in the hippocampus of Fmr1-knockout mice, was corrected by the in vitro application of the selective GABA(B) receptor agonist STX209 (arbaclofen, R-baclofen). STX209 also reduced to wild-type values the elevated AMPA receptor internalization in Fmr1-knockout cultured neurons, a known functional consequence of increased protein synthesis. Acute administration of STX209 in vivo, at doses that modify behavior, decreased mRNA translation in the cortex of Fmr1-knockout mice. Finally, the chronic administration of STX209 in juvenile mice corrected the increased spine density in Fmr1-knockout mice without affecting spine density in wild-type mice. Thus, activation of the GABA(B) receptor with STX209 corrected synaptic abnormalities considered central to fragile X pathophysiology, a finding that suggests that STX209 may be a potentially effective therapy to treat the core symptoms of FXS.

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

“…Specifically, the FXS mouse model (the FMR1 knockout) has shown that FXS can be "cured" (reversal of the excess protein synthesis) of the core phenotype after using agonists of GABA-B receptors [50] or mGluR5 antagonists [48]. To date, a total of 20 double-blind, randomized, placebo-controlled clinical trials in FXS have tested 13 compounds primarily targeting excitatory/inhibitory imbalance theory of FXS and ASD.…”

“…The effort has focused on identifying agents that restore the aforementioned excitatory/inhibitory balance in the FXS brain based on the 'mGluR5 theory,' in which disruptions in mGluR5 signaling are thought to underlie a dendritic pathology [44] and clinical presentations of FXS [14]. Namely, the 'gold-standard' rescue of the dendritic pathology in FXS has been demonstrated in the Fmr1-knockout mouse that largely centered on the use of mGluR5 antagonists [48,49] and GABA-B agonists [50]. These studies of mGluR5 antagonists further support the mGluR5 theory [44].…”

“…As for GABAergic dysfunction, GABA-B agonist arbaclofen reversed many abnormal phenotypes in animal models of FXS [50], presumably by lowering presynaptic glutamate release, resulting in reduction of group mGluR5s signaling. The major progress has then enabled a phase II double-blind placebo-controlled crossover clinical study in which arbaclofen showed improvement over placebo in the social withdrawal problem behaviors efficacy scores.…”

Intervention in the Context of Development: Pathways Toward New Treatments

“…A number of studies have now reported rescue of multiple phenotypes in Fmr1 knockout animals with mGlu5 receptor-negative allosteric modulator drugs with different selectivity at various points in development and with a range of treatment duration (Michalon et al, 2012). Although the mGlu5 theory of FXS has the most support from genetic and pharmacological rescue studies in mice, a number of other potential treatments have also been proposed, including GABA receptor agonists, minocycline, and lithium (Bagni and Oostra, 2013;Gross et al, 2012;Henderson et al, 2012;King and Jope, 2013). With multiple pharmacological approaches rescuing some brain or behavioral phenotypes in Fmr1 knockout animals, the overall data suggest either multiple pathways toward treatment or a lack of specificity to some of these rescued phenotypes.…”

Lifting the Mood on Treating Fragile X

“…The results of this small trial showed beneficial effects on a subset of the adult FXS patients tested; however, it is important to note that no placebo control group was included in this trial, nor was it performed in an experimenter blind fashion (4). Since this initial study, multiple largescale placebo-controlled trials have been initiated with selective mGluR5 negative allosteric modulators-namely, STX107 (Seaside Therapeutics, Cambridge, Massachusetts), RG7090 (Hoffman-LaRoche, Basel, Switzerland), and AFQ056 (Novartis, Basel, Switzerland).…”