title: The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome.
abstract: Previous research indicates that the GABAAergic system is involved in the pathophysiology of the fragile X syndrome, a frequent form of inherited intellectual disability and associated with autism spectrum disorder. However, the molecular mechanism underlying GABAAergic deficits has remained largely unknown. Here, we demonstrate reduced mRNA expression of GABAA receptor subunits in the cortex and cerebellum of young Fmr1 knockout mice. In addition, we show that the previously reported underexpression of specific subunits of the GABAA receptor can be corrected in YAC transgenic rescue mice, containing the full-length human FMR1 gene in an Fmr1 knockout background. Moreover, we demonstrate that FMRP directly binds several GABAA receptor mRNAs. Finally, positive allosteric modulation of GABAA receptors with the neurosteroid ganaxolone can modulate specific behaviors in Fmr1 knockout mice, emphasizing the therapeutic potential of the receptor.
authors: a Department of Medical Genetics ; University of Antwerp ; Antwerp , Belgium.
authors: Sien
authors: S
authors: Braat
authors: a Department of Medical Genetics ; University of Antwerp ; Antwerp , Belgium.|i Present address: Department of Biological Sciences ; Hunter College; City University of New York ; New York , NY USA.
authors: Charlotte
authors: C
authors: D'Hulst
authors: a Department of Medical Genetics ; University of Antwerp ; Antwerp , Belgium.
authors: Inge
authors: I
authors: Heulens
authors: b VIB Department of Molecular and Developmental Genetics ; Molecular Neurobiology; Catholic University Leuven ; Leuven , Belgium.|j Present address: Seaver Autism Centre for Research and Treatment; Icahn School of Medicine at Mount Sinai ; New York , NY USA.
authors: Silvia
authors: S
authors: De Rubeis
authors: c Department of Clinical Genetics ; Erasmus MC Rotterdam ; Rotterdam , The Netherlands.
authors: Edwin
authors: E
authors: Mientjes
authors: d Department of Molecular and Human Genetics ; Baylor College of Medicine; One Baylor Plaza ; Houston , TX USA.
authors: David L
authors: DL
authors: Nelson
authors: c Department of Clinical Genetics ; Erasmus MC Rotterdam ; Rotterdam , The Netherlands.
authors: Rob
authors: R
authors: Willemsen
authors: b VIB Department of Molecular and Developmental Genetics ; Molecular Neurobiology; Catholic University Leuven ; Leuven , Belgium.|e Department of Biomedicine and Prevention ; University of Rome Tor Vergata ; Rome , Italy.
authors: Claudia
authors: C
authors: Bagni
authors: f Laboratory of Neurochemistry and Behaviour; Institute Born-Bunge ; Department of Biomedical Sciences ; University of Antwerp ; Antwerp , Belgium.
authors: Debby
authors: D
authors: Van Dam
authors: f Laboratory of Neurochemistry and Behaviour; Institute Born-Bunge ; Department of Biomedical Sciences ; University of Antwerp ; Antwerp , Belgium.|g Memory clinic; Department of Neurology ; Middelheim General Hospital; ZNA ; Antwerp , Belgium.|h Department of Neurology and Alzheimer Research Centre ; University Medical Centre; Groningen , The Netherlands.
authors: Peter P
authors: PP
authors: De Deyn
authors: a Department of Medical Genetics ; University of Antwerp ; Antwerp , Belgium.
authors: R Frank
authors: RF
authors: Kooy
mesh_terms: D000818:Animals; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005600:Fragile X Syndrome / Q000628:therapy; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011280:Pregnanolone / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D058787:GABA-A Receptor Antagonists; D011280:Pregnanolone; D012333:RNA, Messenger; D011963:Receptors, GABA-A; C497684:Fmr1 protein, mouse; C105051:ganaxolone
keywords: FMRP mRNA target; Fmr1 knockout mouse; GABAA receptor; fragile X syndrome; ganaxolone; targeted therapy