title: The GABA(A) receptor agonist THIP ameliorates specific behavioral deficits in the mouse model of fragile X syndrome.
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.
authors: Center for Neuroscience Research, Children's National Medical Center, Washington, DC, USA.
authors: Jose Luis
authors: JL
authors: Olmos-Serrano
authors: Joshua G
authors: JG
authors: Corbin
authors: Mark P
authors: MP
authors: Burns
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D005239:Fear / Q000187:drug effects; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000503:physiopathology*; D058785:GABA-A Receptor Agonists / Q000627:therapeutic use*; D006801:Humans; D007555:Isoxazoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009483:Neuropsychological Tests; D011963:Receptors, GABA-A / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C497684:Fmr1 protein, mouse; C015542:gaboxadol