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

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.