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.
In this Perspective, Braat and Kooy argue that the GABAergic system is an excellent therapeutic target for neurodevelopmental disorders, including autism and intellectual disability, as it is disturbed in many and because pharmacological intervention is on the shelf.
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, β1 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, β1 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.
•The expression of α2, β1 and δ GABAA receptor subunit mRNA is significantly decreased in young mice.•The expression of GABAA α2, β1 and δ subunits is significantly reduced at the protein level.•Evoked, spontaneous and miniature IPSCs in CA1 pyramidal neurons are reduced.•GABAergic dysfunction contributes to behavioral and cognitive deficits of Fmr1 mice.
The extent to which nanoscale‐engineered systems cross intact human skin and can exert pharmacological effects in viable epidermis is controversial. This research seeks to develop a new lipid‐based ...nanosome that enables the effective delivery of siRNA into human skin. The major finding is that an ultraflexible siRNA‐containing nanosome—prepared using DOTAP, cholesterol, sodium cholate, and 30% ethanol—penetrates into the epidermis of freshly excised intact human skin and is able to enter into the keratinocytes. The nanosomes, called surfactant‐ethanol‐cholesterol‐osomes (SECosomes), show excellent size, surface charge, morphology, deformability, transfection efficiency, stability, and skin penetration capacity after complexation with siRNA. Importantly, these nanosomes have ideal characteristics for siRNA encapsulation, in that the siRNA is stable for at least 4 weeks, they enable highly efficient transfection of in vitro cultured cells, and are shown to transport siRNA delivery through intact human skin where changes in the keratinocyte cell state are demonstrated. It is concluded that increasing flexibility in nanosomes greatly enhances their ability to cross the intact human epidermal membrane and to unload their payload into targeted epidermal cells.
Skin penetration by high molecular weight molecules like siRNA is possible using extreme flexible nanosomes, called SECosomes. At a depth of 40 μm below the skin surface, fluorescently labeled siRNA/SECosome complexes can be detected inside keratinocytes. Fine morphological details of unstained skin are clearly observable with dark nuclei and a granulated pattern in the cell cytoplasm, presumably originated from NADH accumulated in mitochondria.
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.
This article is part of the Special Issue entitled ‘GABAergic Signaling in Health and Disease’.
•Fragile X syndrome is a common cause of intellectual disability and autism.•There is overwhelming evidence for a compromised GABAergic system in animal models.•Preclinical studies led to the initiation of clinical trials in fragile X patients.
An increasing number of studies implicate the GABA sub(A)ergic 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 GABA sub(A) 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 GABA sub(A)ergic deficiency in both animal models have demonstrated that the GABA sub(A) receptor is a promising target for the treatment of fragile X patients. Based on these preclinical studies, clinical trials in patients have been initiated. This article is part of the Special Issue entitled 'GABAergic Signaling in Health and Disease'.
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.
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.
•Fragile X pathophysiological mechanisms were identified in animal models.•Targeted treatments are being developed based on molecular defects.•The first clinical trials in fragile X patients have ...been initiated.
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.
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.
PDF
