Decreased GABA(A) 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 GABA(A) receptor expression in the FVB/N fragile X mouse. Western blot analysis revealed that expression of the GABA(A) receptor beta subunit (GABA(A) beta), 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 GABA(A) beta immunoreactivity. We also found increased expression of glutamic acid decarboxylase, the enzyme responsible for GABA synthesis, in the same regions that showed GABA(A) beta 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.
El Idrissi
Abdeslem
A
Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Rd, Staten Island, NY 10314, USA.
Ding
Xiao-Hua
XH
Scalia
Jason
J
Trenkner
Ekkhart
E
Brown
W Ted
WT
Dobkin
Carl
C
D000818:Animals; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D018345:Mice, Knockout; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D011963:Receptors, GABA-A / Q000096:biosynthesis* / Q000235:genetics; D012640:Seizures / Q000235:genetics / Q000378:metabolism*
C496283:Fxr1h protein, mouse; D016601:RNA-Binding Proteins; D011963:Receptors, GABA-A