Differential translation and fragile X syndrome.
Fragile X syndrome (FXS) is caused by the transcriptional silencing of the Fmr1 gene, which encodes a protein (FMRP) that can act as a translational suppressor in dendrites, and is characterized by a preponderance of abnormally long, thin and tortuous dendritic spines. According to a current theory of FXS, the loss of FMRP expression leads to an exaggeration of translation responses linked to group I metabotropic glutamate receptors. Such responses are involved in the consolidation of a form of long-term depression that is enhanced in Fmr1 knockout mice and in the elongation of dendritic spines, resembling synaptic phenotypes over-represented in fragile X brain. These observations place fragile X research at the heart of a long-standing issue in neuroscience. The consolidation of memory, and several distinct forms of synaptic plasticity considered to be substrates of memory, requires mRNA translation and is associated with changes in spine morphology. A recent convergence of research on FXS and on the involvement of translation in various forms of synaptic plasticity has been very informative on this issue and on mechanisms underlying FXS. Evidence suggests a general relationship in which the receptors that induce distinct forms of efficacy change differentially regulate translation to produce unique spine shapes involved in their consolidation. We discuss several potential mechanisms for differential translation and the notion that FXS represents an exaggeration of one 'channel' in a set of translation-dependent consolidation responses.
Vanderklish
P W
PW
Department of Neurobiology, The Scripps Research Institute, La Jolla, CA 92037, USA. pvanderk@scripps.edu
Edelman
G M
GM
D000818:Animals; D049229:Dendritic Spines / Q000378:metabolism* / Q000473:pathology; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008568:Memory / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000096:biosynthesis / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics
D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D018094:Receptors, Metabotropic Glutamate; C497683:FMR1 protein, human