Trends in Neurosciences
ReviewThe GABAA receptor: a novel target for treatment of fragile X?
Introduction
Fragile X syndrome is the leading cause of inherited mental retardation (reviewed in Refs 1, 2, 3). FMR1 is the causative gene and key issues relate to a lack of mRNA and the absence of the protein product, FMRP 4, 5 (Box 1). Patients suffer from mild to severe cognitive impairment and are characterized by various physical abnormalities, including macroorchidism (enlarged testes) and craniofacial anomalies such as a typical long face, prominent jaws and elongated ears [6]. In addition, individuals with fragile X typically demonstrate a neurobehavioral phenotype that includes autistic and attention-deficit hyperactivity disorder (ADHD) behaviour 6, 7. Sleeping problems and epileptic seizures are common 8, 9.
The generation of animal models has strongly improved our understanding of fragile X syndrome. Fmr1 knockout mice [10] show mild cognitive deficits, hyperactivity, macroorchidism and increased sensitivity to epileptic seizures, features compatible with symptoms observed in fragile X patients 11, 12. Pathological studies in mice revealed long tortuous, immature dendritic spines with increased density along the dendrites, as observed in patients 13, 14. The invertebrate homologue of FMR1 in fruit flies, namely Drosophila melanogaster fragile X mental retardation gene 1 (dFmr1), exhibits high neuronal expression levels. The associated gene product, dFmrp, displays considerable amino acid sequence similarity with the vertebrate FMRP, especially within the functional domains. It possesses similar RNA-binding capacity in addition to the ability to interact with human FMR1, and is required for normal neurite elongation, guidance and branching 15, 16. dFmr1 deficient fly models have been generated that showed behavioural defects such as abnormal eclosion and circadian rhythm and anomalies in the morphology of several central nervous system (CNS) neuronal populations 17, 18, 19.
Here, we present several lines of evidence for involvement of the γ-aminobutyric acid type A (GABAA) receptor (Figure 1) in fragile X syndrome. GABAA receptors are the main inhibitory receptors in the brain, implicated in processes that are also disturbed in fragile X patients, such as anxiety, depression, epilepsy, insomnia, and learning and memory [20]. Therefore, we argue that an altered expression of the GABAA receptor has neurophysiologic and functional consequences that might relate to the behavioural and epileptic phenotype associated with fragile X syndrome. Taking advantage of the well documented GABA pharmacology, we postulate the GABAA receptor as a novel therapeutic target for treatment of specific features of the fragile X phenotype.
Section snippets
Involvement of the GABAergic system in fragile X syndrome
In a genome-wide expression profiling study, differential expression in neurons of fragile X knockout mice was limited to three cDNAs only, including the δ subunit of the GABAA receptor [21]. Subsequently, a significant reduction in the expression of seven other subunits, namely α1, α3 and α4, β1 and β2, and γ1 and γ2, was demonstrated in the cortex of fragile X mice using real-time PCR [22]. In addition to decreased expression of various subunits at the mRNA level, El Idrissi et al. [23]
Phenotypic relationship with the GABAA receptor
Although the physiological consequences of decreased expression of specific GABAA receptor subunits in fragile X patients is unknown, and expression of the GABAB and GABAC receptor has not been investigated, an abnormal function of the GABAA receptor by itself might explain many of the clinical symptoms observed in fragile X patients.
GABAergic system deficiencies in other mental retardation syndromes
Other inborn errors caused by dysfunction of the GABAergic system have features common with fragile X syndrome, further strengthening our hypothesis. Patients with 1p36 deletions, lacking a series of genes including the δ subunit of the GABAA receptor, show neurological and neuropsychiatric anomalies in addition to epilepsy, and it has been suggested that the δ subunit contributes to this phenotype [51]. The genes encoding the α5, β3 and γ3 subunits of the GABAA receptor on chromosome 15 are
Concluding remarks and future perspectives
Ordinarily, excitatory and inhibitory processes exist in balance within the nervous system, resulting in stable, well controlled behaviour. It has previously been suggested that the emerging behavioural and neurocognitive findings pertaining to attentional and social profiles in fragile X syndrome, might be due to core impairments in this delicate balance with subsequent inability to regulate arousal effectively [7]. An excitatory pathway involved in the psychiatric and neurological symptoms
Acknowledgements
We thank Denise Kerstens for help with the graphic design and Wim Van Hul for critical reading of the manuscript. Our fragile X syndrome studies have been supported through grants of the National Fragile X Foundation (NFXF), the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT Vlaanderen), the Belgian National Fund for Scientific Research - Flanders (FWO) and the Fondation Jerôme Lejeune.
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