The Pathophysiology of Fragile X (and What It Teaches Us about Synapses)

• Published in: Annual review of neuroscience Vol. 35; no. 1; pp. 417 - 443
• Main Authors: BHAKAR, Asha L, DÖLEN, Gül, BEAR, Mark F
• Format: Journal Article
• Language: English
• Published: Palo Alto, CA Annual Reviews 01-01-2012; Annual Reviews, Inc
• Subjects: Animals; Autism; Biological and medical sciences; Brain - metabolism; Brain - physiopathology; Child clinical studies; Chromosome fragility (bloom syndrome, ataxia telangiectasia, fanconi anemia, x-linked mental retardation...); Clinical trials; Developmental disorders; Disease Models, Animal; FMR1 protein; fragile X mental retardation protein; Fragile X Mental Retardation Protein - physiology; Fragile X syndrome; Fragile X Syndrome - metabolism; Fragile X Syndrome - physiopathology; Gene Expression Regulation - physiology; Gene silencing; Genetic disorders; Glutamic acid receptors (metabotropic); Humans; Infantile autism; Medical genetics; Medical sciences; Mental retardation; Models, Biological; Nerve Tissue Proteins - biosynthesis; Nervous system; Neuronal Plasticity - physiology; Pathology; Physiology; Plasticity (synaptic); Protein biosynthesis; Protein Biosynthesis - physiology; Protein synthesis; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptors, Metabotropic Glutamate - metabolism; Reviews; RNA - metabolism; Signal transduction; Signal Transduction - physiology; Synapses; Synapses - metabolism; Synapses - physiology; Translation; Chromosome fragility; Translation; Pathophysiology; FMRP; metabotropic glutamate receptor; long-term depression; Developmental disorder; Glutamate receptor; Review; Autism; Synapse; Fragile X mental retardation protein; mRNA translation; Metabotropic receptor; Synaptic transmission; Synaptic plasticity; Synaptic depression; Fragile X syndrome
• ISSN: 0147-006X; 1545-4126
• DOI: 10.1146/annurev-neuro-060909-153138

Fragile X is the most common known inherited cause of intellectual disability and autism, and it typically results from transcriptional silencing of FMR1 and loss of the encoded protein, FMRP (fragile X mental retardation protein). FMRP is an mRNA-binding protein that functions at many synapses to inhibit local translation stimulated by metabotropic glutamate receptors (mGluRs) 1 and 5. Recent studies on the biology of FMRP and the signaling pathways downstream of mGluR1/5 have yielded deeper insight into how synaptic protein synthesis and plasticity are regulated by experience. This new knowledge has also suggested ways that altered signaling and synaptic function can be corrected in fragile X, and human clinical trials based on this information are under way.