title: Expression of the GABAergic system in animal models for fragile X syndrome and fragile X associated tremor/ataxia syndrome (FXTAS).
abstract: After our initial discovery of reduced expression of several subunits of the GABA(A) receptor in two different animal models for fragile X syndrome, a frequent form of inherited mental retardation, we analyzed further components of the GABAergic pathway. Interestingly, we found a down regulation of many additional elements of the GABA signalling system, strengthening our hypothesis of involvement of the GABAergic pathway in the pathophysiology of fragile X syndrome. This is of special interest with regard to new therapeutic opportunities for treatment of this disorder. Remarkably, under expression was predominantly observed in cortex, although some elements of the GABAergic system that are expressed presynaptically or in the glial cells were also down regulated in the cerebellum. Additionally, we assessed the GABAergic system in expanded CGG-repeat mice, a model for fragile X associated tremor/ataxia syndrome (FXTAS). This late onset neurodegenerative disorder occurs in carriers of the fragile X premutation (55-200 CGG repeats) and is completely distinct (from both clinical and molecular pathogenic perspectives) from the neurodevelopmental disorder fragile X syndrome. Here we found upregulation of many components of the GABAergic system in cerebellum, but not in cortex. This finding is consistent with the cerebellar phenotype of FXTAS patients and has implications for the mechanism causative of differential gene expression.
authors.affiliation: Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, Antwerp, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: D'Hulst
authors.forename: Inge
authors.initials: I
authors.lastname: Heulens
authors.forename: Judith R
authors.initials: JR
authors.lastname: Brouwer
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.forename: Natalie
authors.initials: N
authors.lastname: De Geest
authors.forename: Simon P
authors.initials: SP
authors.lastname: Reeve
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Bassem A
authors.initials: BA
authors.lastname: Hassan
authors.forename: R Frank
authors.initials: RF
authors.lastname: Kooy
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D005075:Biological Evolution; D002531:Cerebellum / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012313:RNA / Q000096:biosynthesis; D015398:Signal Transduction; D019680:Trinucleotide Repeat Expansion; D015854:Up-Regulation; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D012313:RNA; D005680:gamma-Aminobutyric Acid; C467328:FMR1 protein, Drosophila; C497684:Fmr1 protein, mouse