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. 2011;33(5):395-403.
doi: 10.1159/000332884. Epub 2011 Nov 8.

The GABA(A) receptor agonist THIP ameliorates specific behavioral deficits in the mouse model of fragile X syndrome

Jose Luis Olmos-Serrano  1 , Joshua G Corbin, Mark P Burns
Affiliations

The GABA(A) receptor agonist THIP ameliorates specific behavioral deficits in the mouse model of fragile X syndrome

Jose Luis Olmos-Serrano et al. Dev Neurosci. 2011.

Abstract

Hyperactivity, hypersensitivity to auditory stimuli, and exaggerated fear are common behavioral abnormalities observed in individuals with fragile X syndrome (FXS), a neurodevelopmental disorder that is the most common genetic cause of autism. Evidence from studies of the Fmr1 knockout (KO) mouse model of FXS supports the notion that impaired GABAergic transmission in different brain regions such as the amygdala, striatum or cerebral cortex is central to FXS behavioral abnormalities. This suggests that the GABAergic system might be an intriguing target to ameliorate some of the phenotypes in FXS. Our recent work revealed that THIP (gaboxadol), a GABA(A) receptor agonist, can restore principal neuron excitability deficits in the Fmr1 KO amygdala, suggesting that THIP may also restore some of the key behavioral abnormalities in Fmr1 KO mice. Here, we reveal that THIP significantly attenuated hyperactivity in Fmr1 KO mice, and reduced prepulse inhibition in a volume-dependent manner. In contrast, THIP did not reverse the deficits in cued fear or startle response. Thus, this study shows that enhancing GABAergic transmission can correct specific behavioral phenotypes of the Fmr1 KO mouse further supporting that targeting the GABAergic system, and specifically tonic inhibition, might be important for correcting or ameliorating some key behaviors in FXS.

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Figures

Fig. 1
Fig. 1
THIP prevents hyperactivity in Fmr1 KO mice. Distance travelled (a) and average velocity (b) of WT and Fmr1 KO mice in an open field test. Mice were tracked using a video-monitoring system over a 30-min period. * p < 0.05 vs. WT control; # p < 0.05 vs. Fmr1 KO control. ANOVA and Newman Keuls post hoc. n = 8 per group.
Fig. 2
Fig. 2
Fmr1 KO mice have decreased cued, but not contextual, fear conditioning. a Acquisition of conditioned fear in WT and Fmr1 KO mice. Freeze time was measured as a percent of the trial block (2 min). Three shocks were presented to the mice followed by a 2-min interval. b Percent freeze time in contextual and cued testing 24–26 h after training. * p < 0.05, unpaired t test. c The effects of THIP administration 30 min prior to cued fear testing. * p < 0.05 vs. Fmr1 KO (control). ANOVA and Newman Keuls post hoc. n = 8 per group.
Fig. 3
Fig. 3
THIP attenuates the Fmr1 KO-induced increase in PPI. a The startle response of WT and Fmr1 KO mice to a 120-dB white noise pulse is not affected by THIP treatment 30 min prior to entering the sound chamber. b PPI is significantly increased in Fmr1 KO mice compared to WT controls. The greatest difference between genotypes is observed with the lower decibel prepulses. This effect is blunted in THIP-treated mice, but only at low decibel prepulses. The x-axis displays prepulse in dB above background (65 dB). ** p < 0.01; *** p < 0.001; n.s. = non-significant vs. WT (control). # p < 0.05; ## p < 0.01; ### p < 0.001; n.s. = non-significant vs. WT (THIP). ANOVA with Newman Keuls post hoc (performed individually for each prepulse volume). c Change in PPI in Fmr1 KO mice as a percentage of WT mice. WT mouse response was set at 100%. THIP-treated Fmr1 KO mice were compared to THIP-treated WT mice. Fmr1 KO control mice were compared to WT control mice. * p < 0.05; ** p < 0.01, unpaired t test. Fmr1 KO (control) vs. Fmr1 KO (THIP). n = 8 per group.
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