The GABA(A) receptor is an FMRP target with therapeutic potential in fragile X syndrome

Sien Braat, Charlotte D'Hulst, Inge Heulens, Silvia De Rubeis, Edwin Mientjes, David L. Nelson, Rob Willemsen, Claudia Bagni, Debby Van Dam, Peter P. De Deyn, R. Frank Kooy*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    78 Citations (Scopus)

    Abstract

    Previous research indicates that the GABA(A)ergic 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 GABA(A)ergic deficits has remained largely unknown. Here, we demonstrate reduced mRNA expression of GABA(A) 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 GABA(A) 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 GABA(A) receptor mRNAs. Finally, positive allosteric modulation of GABA(A) receptors with the neurosteroid ganaxolone can modulate specific behaviors in Fmr1 knockout mice, emphasizing the therapeutic potential of the receptor.

    Original languageEnglish
    Pages (from-to)2985-2995
    Number of pages11
    JournalCell Cycle
    Volume14
    Issue number18
    DOIs
    Publication statusPublished - 17-Sept-2015

    Keywords

    • FMRP mRNA target
    • Fmr1 knockout mouse
    • fragile X syndrome
    • GABA(A) receptor
    • ganaxolone
    • targeted therapy
    • MENTAL-RETARDATION PROTEIN
    • SENSORIMOTOR GATING ABNORMALITIES
    • ACOUSTIC STARTLE RESPONSE
    • KNOCKOUT MOUSE MODEL
    • MESSENGER-RNAS
    • MICE
    • EXPRESSION
    • GANAXOLONE
    • MECHANISMS
    • SEQUENCES

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