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.

Braat, S., D'Hulst, C., Heulens, I., de Rubeis, S., Mientjes, E., Nelson, D., et al. (2015). The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome. CELL CYCLE, 14(18), 2985-2995 [10.4161/15384101.2014.989114].

The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome

BAGNI, CLAUDIA
Membro del Collaboration Group
;
2015-01-01

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.
2015
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/13 - BIOLOGIA APPLICATA
English
FMRP mRNA target; Fmr1 knockout mouse; GABAA receptor; fragile X syndrome; ganaxolone; targeted therapy
Braat, S., D'Hulst, C., Heulens, I., de Rubeis, S., Mientjes, E., Nelson, D., et al. (2015). The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome. CELL CYCLE, 14(18), 2985-2995 [10.4161/15384101.2014.989114].
Braat, S; D'Hulst, C; Heulens, I; de Rubeis, S; Mientjes, E; Nelson, D; Willemsen, R; Bagni, C; van Dam, D; de Deyn, P; Kooy, R
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/238825
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