Abstract
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and autism. FXS is also accompanied by attention problems, hyperactivity, anxiety, aggression, poor sleep, repetitive behaviors, and self-injury. Recent work supports the role of γ-aminobutyric-acid (GABA), the primary inhibitory neurotransmitter in the brain, in mediating symptoms of FXS. Deficits in GABA machinery have been observed in a mouse model of FXS, including a loss of tonic inhibition in the amygdala, which is mediated by extrasynaptic GABAA receptors. Humans with FXS also show reduced GABAA receptor availability. Here, we sought to evaluate the potential of gaboxadol (also called OV101 and THIP), a selective and potent agonist for delta-subunit-containing extrasynaptic GABAA receptors (dSEGA), as a therapeutic agent for FXS by assessing its ability to normalize aberrant behaviors in a relatively uncharacterized mouse model of FXS (Fmr1 KO2 mice). Four behavioral domains (hyperactivity, anxiety, aggression, and repetitive behaviors) were probed using a battery of behavioral assays. The results showed that Fmr1 KO2 mice were hyperactive, had abnormal anxiety-like behavior, were more irritable and aggressive, and had an increased frequency of repetitive behaviors compared to wild-type (WT) littermates, which are all behavioral deficits reminiscent of individuals with FXS. Treatment with gaboxadol normalized all of the aberrant behaviors observed in Fmr1 KO2 mice back to WT levels, providing evidence of its potential benefit for treating FXS. We show that the potentiation of extrasynaptic GABA receptors alone, by gaboxadol, is sufficient to normalize numerous behavioral deficits in the FXS model using endpoints that are directly translatable to the clinical presentation of FXS. Taken together, these data support the future evaluation of gaboxadol in individuals with FXS, particularly with regard to symptoms of hyperactivity, anxiety, irritability, aggression, and repetitive behaviors.
Highlights
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and autism with an estimated frequency of 1:4,000–5,000, affecting all ethnic groups worldwide (Gross et al, 2015)
To test whether the Fmr1 KO2 mice showed locomotor hyperactivity and whether gaboxadol could normalize this aberrant behavior, Fmr1 KO2 mice were injected with vehicle or gaboxadol (0.5–5 mg/kg, i.p.), and WT littermates were injected with vehicle 30 min before testing in the Open Field Test (OFT)
The results showed that the distance traveled by Fmr1 KO2 mice was significantly increased compared to WT littermate controls (Figure 1, F(8,81) = 21.27, p < 0.0001), consistent with results from other models of FXS
Summary
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and autism with an estimated frequency of 1:4,000–5,000, affecting all ethnic groups worldwide (Gross et al, 2015). The role of FMRP in FXS and evaluation of candidate therapeutics has been studied in large part through the use of an Fmr knockout (KO) mouse model first characterized by the Dutch-Belgian Fragile X Consortium (Bakker et al, 1994). The Fmr KO was generated by a targeted insertion of a neomycin cassette into exon 5 of the FMR1 gene, resulting in a mouse that had undetectable levels FMRP protein and low levels of residual Fmr mRNA (Bakker et al, 1994). The Fmr KO2 mouse targets a new null allele at Fmr generated by deletion of the promoter and first exon of Fmr (Mientjes et al, 2006). It is both protein and mRNA null. At the cellular and circuit levels, studies of the FXS mice have focused largely on overactive metabotropic glutamate receptor 5 (mGluR5) signaling (Dölen et al, 2007), increased protein synthesis (Osterweil et al, 2010), and enhanced long-term potentiation (LTP; Auerbach and Bear, 2010)
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