The GABA_A receptor is an FMRP target with therapeutic potential in fragile X syndrome

Abstract

Previous research indicates that the GABAAergic system is involved in the pathophysiology of the fragile X syndrome, a frequent form of inherited intellectual disability and associated with autism spectrum disorder. However, the molecular mechanism underlying GABAAergic deficits has remained largely unknown. Here, we demonstrate reduced mRNA expression of GABAA receptor subunits in the cortex and cerebellum of young Fmr1 knockout mice. In addition, we show that the previously reported underexpression of specific subunits of the GABAA receptor can be corrected in YAC transgenic rescue mice, containing the full-length human FMR1 gene in an Fmr1 knockout background. Moreover, we demonstrate that FMRP directly binds several GABAA receptor mRNAs. Finally, positive allosteric modulation of GABAA receptors with the neurosteroid ganaxolone can modulate specific behaviors in Fmr1 knockout mice, emphasizing the therapeutic potential of the receptor.

Psychosis and catatonia in fragile X: Case report and literature review

“…There is a considerable risk of mortality in individuals who develop malignant catatonia/NMS which is known to present with severe functional impairment, autonomic and cardiovascular instability, reduced food and fluid intake resulting in dehydration, weight loss, multi-organ failure and other medical complications (41). The neurochemical pathology of catatonia includes decreased GABA activity and up-regulation of the glutamate system, both of which occur in those with a premutation and a full mutation (22,67,68).…”

Review of targeted treatments in fragile X syndrome

“…GABA A receptors are reduced in the neocortex, cerebellum, and hippocampus of the Fmr1 KO mouse with deficits more pronounced at younger ages (27,34,35). These receptors consist of multiple subunits, and those containing an extrasynaptic δ-subunit are diminished by 50% in certain areas of the KO mouse brain (29).…”

“…Further, PET imaging in human subjects with FXS indicate significant reductions in GABA A receptor availability throughout the CNS (36), which suggests the GABA A deficit is not simply an artifact of the KO mouse. Trials of GABA A agonists in animal models have shown positive results by restoring neuronal excitability in the amygdala to normal levels, mitigating anxiety and hyperactive behaviors, and rescuing the audiogenic seizure phenotype (30,33,34). Neuroactive steroids, in particular, could be well suited to treat FXS because they potentiate the effects of GABA A receptors containing the δ-subunit.…”

“…It is well tolerated in both pediatric and adult populations, and initial trials in the KO mouse have specifically improved seizures and showed a dose-dependent reduction in stereotypic and repetitive behaviors (30,34). Moreover, unlike benzodiazepines which also target GABA receptors, ganaxolone does not show tolerance allowing potential for long-term use (37).…”

“…These receptors consist of multiple subunits, and those containing an extrasynaptic δ-subunit are diminished by 50% in certain areas of the KO mouse brain (29). FMRP has been shown to directly bind to mRNA encoding for GABA A subunits serving as a possible stabilization factor, and reintroduction of FMRP can correct δ-subunit mRNA to normal levels (34). Further, PET imaging in human subjects with FXS indicate significant reductions in GABA A receptor availability throughout the CNS (36), which suggests the GABA A deficit is not simply an artifact of the KO mouse.…”