title: Fragile X protein FMRP is required for homeostatic plasticity and regulation of synaptic strength by retinoic acid.
abstract: Homeostatic synaptic plasticity adjusts the strength of synapses during global changes in neural activity, thereby stabilizing the overall activity of neural networks. Suppression of synaptic activity increases synaptic strength by inducing synthesis of retinoic acid (RA), which activates postsynaptic synthesis of AMPA-type glutamate receptors (AMPARs) in dendrites and promotes synaptic insertion of newly synthesized AMPARs. Here, we show that fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates dendritic protein synthesis, is essential for increases in synaptic strength induced by RA or by blockade of neural activity in the mouse hippocampus. Although activity-dependent RA synthesis is maintained in Fmr1 knock-out neurons, RA-dependent dendritic translation of GluR1-type AMPA receptors is impaired. Intriguingly, FMRP is only required for the form of homeostatic plasticity that is dependent on both RA signaling and local protein synthesis. Postsynaptic expression of wild-type or mutant FMRP(I304N) in knock-out neurons reduced the total, surface, and synaptic levels of AMPARs, implying a role for FMRP in regulating AMPAR abundance. Expression of FMRP lacking the RGG box RNA-binding domain had no effect on AMPAR levels. Importantly, postsynaptic expression of wild-type FMRP, but not FMRP(I304N) or FMRPΔRGG, restored synaptic scaling when expressed in knock-out neurons. Together, these findings identify an unanticipated role for FMRP in regulating homeostatic synaptic plasticity downstream of RA. Our results raise the possibility that at least some of the symptoms of fragile X syndrome reflect impaired homeostatic plasticity and impaired RA signaling.
authors.affiliation: Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California 94720-3200, USA.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Soden
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D003712:Dendrites / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D014176:Protein Biosynthesis / Q000502:physiology; D018091:Receptors, AMPA / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis; D000072482:Retinoic Acid Receptor alpha; D013569:Synapses / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; C497684:Fmr1 protein, mouse; C000607072:Rara protein, mouse