TY - JOUR T1 - Inactivation of the Maternal Fragile X Gene Results in Sensitization of GABA<sub>B</sub> Receptor Function in the Offspring JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 820 LP - 826 DO - 10.1124/jpet.108.143990 VL - 327 IS - 3 AU - Bojana Zupan AU - Miklos Toth Y1 - 2008/12/01 UR - http://jpet.aspetjournals.org/content/327/3/820.abstract N2 - Fragile X syndrome is an X-linked disorder caused by the inactivation of the FMR1 gene, with symptoms ranging from impaired cognitive functions to seizures, anxiety, sensory abnormalities, and hyperactivity. Although fragile X syndrome is considered a typical Mendelian disorder, we have recently reported that the environment, specifically the fmr1+/- or fmr1-/- [H or knockout (KO)] maternal environment, elicits on its own a partial fragile X-like phenotype and can contribute to the overall phenotype of fmr1-/0 (KO) male offspring. Genetically fmr1+/0 (WT) males born to H females (Hmaternal &gt; WToffspring), similar to KO male offspring born to H and KO mothers (H &gt; KO and KO &gt; KO), exhibit locomotor hyperactivity. These mice also showed reduced D2 autoreceptor function, indicating a possible diminished feedback inhibition of dopamine (DA) release in the nigrostriatal and mesolimbic systems. The GABAergic system also regulates DA release, in part via presynaptic GABAB receptors (Rs) located on midbrain dopaminergic neurons. Here, we show that the locomotor inhibitory effect of the GABABR agonist baclofen [4-amino-3-(4-chlorophenyl)-butanoic acid] is enhanced in all progeny of mutant mothers (H &gt; WT, H &gt; KO, and KO &gt; KO) compared with WT &gt; WT mice, irrespective of their own genotype. However, increased sensitivity to baclofen was selective and limited to the locomotor response because the muscle-relaxant and sedative effects of the drug were not altered by the maternal environment. These data show that GABABR sensitization, traditionally induced pharmacologically, can also be elicited by the fmr1-deficient maternal environment. The American Society for Pharmacology and Experimental Therapeutics ER -