Decreased expression of the GABAA receptor in fragile X syndrome

• Published in: Brain research Vol. 1121; no. 1; pp. 238 - 245
• Main Authors: D'HULST, Charlotte, DE GEEST, Natalie, REEUE, Simon P, VAN DAM, Debby, DE DEVN, Peter P, HASSAN, Bassem A, KOOY, R. Frank
• Format: Journal Article
• Language: English
• Published: London Elsevier 22.11.2006; Amsterdam; New York, NY
• Subjects: Animals; Biological and medical sciences; Chromosome fragility (bloom syndrome, ataxia telangiectasia, fanconi anemia, x-linked mental retardation...); Crosses, Genetic; Disease Models, Animal; Down-Regulation; Fragile X Mental Retardation Protein - genetics; Fragile X Syndrome - genetics; Gene Expression Regulation; Humans; Male; Medical genetics; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Receptors, GABA-A - genetics; RNA, Messenger - genetics; Chromosome fragility; Fragile X fly model; Rodentia; Fragile X knockout mouse; Polymerase chain reaction; Vertebrata; Mammalia; Mouse; Real-time PCR; Animal; Models; Mutation; Fragile X syndrome; GABAA receptor; Gabaergic receptor A
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2006.08.115

After our initial discovery of under expression of the GABA(A) receptor delta subunit in a genome wide screening for differentially expressed mRNAs in brain of fragile X mice, a validated model for fragile X mental retardation syndrome, we analyzed expression of the 17 remaining subunits of the GABA(A) receptor using real-time PCR. We confirmed nearly 50% under expression of the delta subunit and found a significant 35%-50% reduction in expression of 7 additional subunit mRNAs, namely alpha(1), alpha(3), and alpha(4), beta(1) and beta(2) and gamma(1) and gamma(2), in fragile X mice compared to wild-type littermates. In concordance with previous results, under expression was found in cortex, but not in cerebellum. Moreover, decreased expression of specific GABA(A) receptor subunits in fragile X syndrome seems to be an evolutionary conserved hallmark since in the fragile X fly (Drosophila melanogaster) model we also found almost 50% under expression of all 3 subunits which make up the invertebrate GABA receptor, namely Grd, Rdl and Lcch3. In addition, we demonstrated a direct correlation between the amount of dFmrp and the expression of the GABA receptor subunits Rdl and Grd. Our results add evidence to previous observations of an altered GABAergic system in fragile X syndrome. Because GABA(A) receptors are the major inhibitory receptors in brain, involved in anxiety, depression, insomnia, learning and memory and epilepsy, processes also disturbed in fragile X patients, the well described GABA(A) receptor pharmacology might open new powerful opportunities for treatment of the behavioral and epileptic phenotype associated with fragile X syndrome.