Elsevier

Neuroscience Letters

Volume 377, Issue 3, 4 April 2005, Pages 141-146
Neuroscience Letters

Decreased GABAA receptor expression in the seizure-prone fragile X mouse

https://doi.org/10.1016/j.neulet.2004.11.087Get rights and content

Abstract

The fragile X mental retardation syndrome is due to the transcriptional silence of the fragile X gene, FMR1, and to the resulting loss of the FMR1 product, FMRP. The pathogenesis of the syndrome, however, is not understood. Increased prevalence of childhood seizures is a feature of the fragile X syndrome and increased seizure susceptibility is seen in the fragile X knock out mouse model for this disorder. To investigate the increased seizure susceptibility, we examined GABAA receptor expression in the FVB/N fragile X mouse. Western blot analysis revealed that expression of the GABAA receptor β subunit (GABAA β), which is required for receptor function, was reduced in the cortex, hippocampus, diencephalon and brainstem in adult male fragile X mice. Immunohistochemical analysis of brain sections indicated a reduction in GABAA β immunoreactivity. We also found increased expression of glutamic acid decarboxylase, the enzyme responsible for GABA synthesis, in the same regions that showed GABAA β reduction. These results indicate that the absence of Fmrp leads to GABAergic system alterations that could account for the increased seizure susceptibility of the fragile X mouse. These alterations may also be relevant to the seizures and the abnormal behaviors in the human syndrome.

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Acknowledgements

This work was supported in part by funds from the New York State Office of Mental Retardation and Developmental Disabilities and in part by grants (W.T.B. and C.D.) from the FRAXA Foundation.

References (34)

  • K.Y. Miyashiro et al.

    RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice

    Neuron

    (2003)
  • M. Ramirez et al.

    Activity-dependent expression of GAD67 in the granule cells of the rat hippocampus.

    Brain Res.

    (2001)
  • A. Schenck et al.

    CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X protein

    Neuron

    (2003)
  • H. Siomi et al.

    The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein

    Cell

    (1993)
  • Y.Q. Zhang et al.

    Drosophila fragile X-related gene regulates the MA:1B homolog Futsch to control synaptic structure and function

    Cell

    (2001)
  • C.E. Bakker et al.

    Fmr1 knockout mice: a model to study fragile X mental retardation

    Cell

    (1994)
  • B. Bardoni et al.

    Advances in understanding of fragile X pathogenesis and FMRP function, and in identification of X linked mental retardation genes

    Curr. Opin. Genet. Dev.

    (2002)
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