Involvement and therapeutic potential of the GABAergic system in the fragile X syndrome.

Many drugs have been developed that are able to modulate the GABAergic system, which is involved in anxiety, depression, epilepsy, insomnia, and learning and memory. The recent observation that the GABA(A) receptor is underexpressed in the fragile X syndrome, an inherited mental retardation disorder, therefore raised hopes for targeted therapy of the disorder. This review summarizes the lines of evidence that demonstrate a malfunction of the GABAergic system. The GABAergic system clearly emerges as an attractive target for therapy of the fragile X syndrome, and thus provides an excellent example of how genetic research can lead to unique opportunities for treatment.

Impaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice.

Many clinical and molecular features of the fragile X syndrome, a common form of intellectual disability and autism, can be modeled by deletion of the Fmr1 protein (Fmrp) in mice. Previous studies showed a decreased expression of several components of the GABAergic system in Fmr1 knockout mice. Here, we used this mouse model to investigate the functional consequences of Fmrp deletion on hippocampal GABAergic inhibition in the CA1-region of the hippocampus. Whole-cell patch-clamp recordings demonstrated a significantly reduced amplitude of evoked inhibitory postsynaptic currents (eIPSCs) and a decrease in the amplitude and frequency of spontaneous IPSCs. In addition, miniature IPSCs were reduced in amplitude and frequency and decayed significantly slower than mIPSCs in controls. Quantitative real-time PCR revealed a significantly lower expression of α2, ß1 and δ GABAA receptor subunits in the hippocampus of the juvenile mice (P22) compared to wild-type littermates. Correspondingly, we found also at the protein level reduced amounts of α2, ß1 and δ subunits in Fmr1 knockout mice. Overall, these results demonstrate that the reduction in several components of the GABAergic system is already present at young age and that this reduction results in measurable abnormalities on GABAA receptor-mediated phasic inhibition. These abnormalities might contribute to the behavioral and cognitive deficits of this fragile X mouse model.

Insights into GABAAergic system deficits in fragile X syndrome lead to clinical trials.

An increasing number of studies implicate the GABAAergic system in the pathophysiology of the fragile X syndrome, a frequent cause of intellectual disability and autism. Animal models have proven invaluable in unravelling the molecular mechanisms underlying the disorder. Multiple defects in this inhibitory system have been identified in Fmr1 knockout mice, including altered expression of various components, aberrant GABAA receptor-mediated signalling, altered GABA concentrations and anatomical defects in GABAergic neurons. Aberrations compatible with those described in the mouse model were detected in dfmr1 deficient Drosophila melanogaster, a validated fly model for the fragile X syndrome. Treatment with drugs that ameliorate the GABAAergic deficiency in both animal models have demonstrated that the GABAA receptor is a promising target for the treatment of fragile X patients. Based on these preclinical studies, clinical trials in patients have been initiated.

The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders.

Intellectual disability, autism spectrum disorder, and epilepsy are prime examples of neurodevelopmental disorders that collectively affect a significant percentage of the world population. Recent technological breakthroughs allowed the elucidation of the genetic causes of many of these disorders. As neurodevelopmental disorders are genetically heterogeneous, the development of rational therapy is extremely challenging. Fortunately, many causative genes are interconnected and cluster in specific cellular pathways. Targeting a common node in such a network would allow us to interfere with a series of related neurodevelopmental disorders at once. Here, we argue that the GABAergic system is disturbed in many neurodevelopmental disorders, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and is a key candidate target for therapeutic intervention. Many drugs that modulate the GABAergic system have already been tested in animal models with encouraging outcomes and are readily available for clinical trials.

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

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.

Fragile X syndrome neurobiology translates into rational therapy.

Causal genetic defects have been identified for various neurodevelopmental disorders. A key example in this respect is fragile X syndrome, one of the most frequent genetic causes of intellectual disability and autism. Since the discovery of the causal gene, insights into the underlying pathophysiological mechanisms have increased exponentially. Over the past years, defects were discovered in pathways that are potentially amendable by pharmacological treatment. These findings have inspired the initiation of clinical trials in patients. The targeted pathways converge in part with those of related neurodevelopmental disorders raising hopes that the treatments developed for this specific disorder might be more broadly applicable.

Metabonomics adds a new dimension to fragile X syndrome.

Fragile X syndrome is the most common cause of inherited intellectual disability, but the underlying pathophysiology is complex and effective treatments are lacking. In a recent study of fragile X mental retardation 1 (Fmr1) knockout mice, the metabolic profile of the fragile X brain was determined using proton high-resolution magic angle spinning nuclear magnetic resonance spectroscopy. This analysis revealed deficiencies in four metabolic categories: neurotransmission, osmoregulation, energy metabolism and oxidative stress response. Abnormalities in the metabolic phenotype were linked to the fragile X mental retardation protein using an integrated metabolome and interactome mapping approach, allowing a global picture of the disorder to emerge.