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

Abstract

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.00730.2012The fragile X syndrome is a mutationdriven 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.

Developmental profiles of infants with an FMR1 premutation

“…The hyperresponsive behavior is thought to be related to a lack of GABA inhibition which causes a lack of habituation to sensory stimuli seen in children with FXS [58]. GABA deficits have not only been documented in FXS but also in those with the premutation [59]. …”

Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome

“…12 Deficits in FMRP lead to up-regulation of the mGluR5 system 33 and down-regulation of the GABA A system, 34 resulting in an excitatory/inhibitory imbalance that is observed in the premutation mouse-model neurons. 35 In this regard, a recent transcranial magnetic stimulation (TMS) study 36 demonstrated that asymptomatic adult women with the premutation have reduced GABA A -mediated intracortical and afferent inhibition from the cerebellum to the primary motor cortex, compared to age-matched controls. It is possible that these GABA A deficits predispose carriers to the ADHD symptoms experienced by approximately 30% of boys with the premutation.…”

“…The observation that allopregnanolone normalizes network activity in neurons cultured from premutation mice, 35 coupled with the observed GABA A deficit in FXTAS patients, 36 suggests that a GABA A agonist will be beneficial to those with FXTAS. Moreover, at the cellular level, an mGluR5 antagonist similarly improved neuronal network activity, 35 pointing to an excitatory/inhibitory imbalance that is reminiscent of FXS.…”

The contribution of inhibitory interneurons to circuit dysfunction in Fragile X Syndrome

“…For instance, lack of FMRP found in the mouse model of FXS leads to cerebellar deficits at both the cellular and behavioral levels and raise the possibility that cerebellar dysfunctions can contribute to motor learning deficits in FXS patients (Koekkoek et al, 2005). Indeed, although premutation carriers of FMRP lead to a different syndrome (FXTAS), they showed an absence of cerebellar inhibition over primary motor cortex and a reduced GABA-mediated intracortical and afferent inhibition compared with healthy individuals (Conde et al, 2013) that could potentially also be present in FXS patients. Moreover, FXS patients display specific emotion recognition deficits for angry and neutral (but not happy or fearful) facial expressions through visual scanning tasks (Shaw and Porter, 2013), that in turn is directly related to formation and function of neuronal circuits attributed to behavioral processes such as fear, emotion recognition and anxiety carried out by the amygdala (Olmos-Serrano and Corbin, 2011; Kim et al, 2014).…”