Abnormal GABA-mediated and cerebellar inhibition in women with the fragile X premutation

Conde V, Palomar FJ, Lama MJ, Martinez R, Carrillo F, Pintado E, Mir P. Abnormal GABA-mediated and cerebellar inhibition in women with the fragile X premutation. J Neurophysiol 109: 1315-1322, 2013. First published December 12, 2012; doi:10.1152/jn.00730.2012.-The fragile X syndrome is a mutation-driven developmental disorder caused by a repetition over 200 times of the CGG trinucleotide situated in the 5'-untranslated region of the fragile X mental retardation 1 gene (FMR1). The interval between 55 and 199 CGG repeats, which is over the normal range but below full mutation, is named fragile X premutation. Recent studies have focused on the asymptomatic state of fragile X premutation carriers and their potentially relevant preclinical features. However, the underlying neurological mechanisms leading to altered functions in fragile X premutation carriers are still poorly understood. In this study, we wanted to test the hypothesis that asymptomatic women who carry the fragile X premutation present GABAergic and cerebellar abnormalities compared with healthy women without the premutation. We performed noninvasive brain stimulation protocols on both asymptomatic fragile X premutation carriers and controls comprising of measures of GABA(A)- and GABA(B)-mediated intracortical inhibition, afferent inhibition, and cerebello-motor functional interactions. Premutation carriers presented an absence of cerebellar inhibition over primary motor cortex as well as a reduced GABA(A)-mediated intracortical and afferent inhibition compared with healthy nonpremutated controls. These alterations are most probably dependent on a dysfunctional GABAergic mechanism associated with the fragile X premutation condition as previously found in CGG-repeat animal models. Furthermore, the lack of cerebello-motor inhibition could be related to the cerebellar structural abnormalities previously found in carriers of the premutation.