title: Inactivation of the maternal fragile X gene results in sensitization of GABAB receptor function in the offspring.
abstract: 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 (H(maternal) > WT(offspring)), similar to KO male offspring born to H and KO mothers (H > KO and KO > KO), exhibit locomotor hyperactivity. These mice also showed reduced D(2) 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 GABA(B) receptors (Rs) located on midbrain dopaminergic neurons. Here, we show that the locomotor inhibitory effect of the GABA(B)R agonist baclofen [4-amino-3-(4-chlorophenyl)-butanoic acid] is enhanced in all progeny of mutant mothers (H > WT, H > KO, and KO > KO) compared with WT > 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 GABA(B)R sensitization, traditionally induced pharmacologically, can also be elicited by the fmr1-deficient maternal environment.
authors.affiliation: Weill Cornell Graduate School of Medical Sciences, Cornell University, Neuroscience Program, New York, New York, USA.
authors.forename: Bojana
authors.initials: B
authors.lastname: Zupan
authors.forename: Miklos
authors.initials: M
authors.lastname: Toth
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D040582:Inheritance Patterns; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009035:Mothers; D009043:Motor Activity; D010641:Phenotype; D018080:Receptors, GABA-B / Q000502:physiology*
chemical_list: D001418:Baclofen; D051860:Fragile X Messenger Ribonucleoprotein 1; D018080:Receptors, GABA-B; C497684:Fmr1 protein, mouse