title: Rescue of Synaptic Phenotypes and Spatial Memory in Young Fragile X Mice.
abstract: Fragile X syndrome (FXS) is characterized by synaptic immaturity, cognitive impairment, and behavioral changes. The disorder is caused by transcriptional shutdown in neurons of thefragile X mental retardation 1gene product, fragile X mental retardation protein. Fragile X mental retardation protein is a repressor of dendritic mRNA translation and its silencing leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, and FXS is a disorder that currently has no effective therapeutics. Here, young fragile X mice were treated with chronic bryostatin-1, a relatively selective protein kinase Cεactivator, which induces synaptogenesis and synaptic maturation/repair. Chronic treatment with bryostatin-1 rescues young fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in 1) hippocampal brain-derived neurotrophic factor expression, 2) postsynaptic density-95 levels, 3) transformation of immature dendritic spines to mature synapses, 4) densities of the presynaptic and postsynaptic membranes, and 5) spatial learning and memory. The therapeutic effects were achieved without downregulation of metabotropic glutamate receptor (mGluR) 5 in the hippocampus and are more dramatic than those of a late-onset treatment in adult fragile X mice. mGluR5 expression was in fact lower in fragile X mice and its expression was restored with the bryostatin-1 treatment. Our results show that synaptic and cognitive function of young FXS mice can be normalized through pharmacological treatment without downregulation of mGluR5 and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation at a young age and in adults.
authors.affiliation: Blanchette Rockefeller Neurosciences Institute, Morgantown, West Virginia masun@brni.org mksun@brni-jhu.org.
authors.forename: Miao-Kun
authors.initials: MK
authors.lastname: Sun
authors.affiliation: Blanchette Rockefeller Neurosciences Institute, Morgantown, West Virginia.
authors.forename: Jarin
authors.initials: J
authors.lastname: Hongpaisan
authors.affiliation: Blanchette Rockefeller Neurosciences Institute, Morgantown, West Virginia.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Alkon
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D054713:Bryostatins / Q000494:pharmacology; D049229:Dendritic Spines / Q000187:drug effects; D000076122:Disks Large Homolog 4 Protein; D020536:Enzyme Activators / Q000494:pharmacology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology; D051379:Mice; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000187:drug effects; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D017661:Receptors, Presynaptic / Q000187:drug effects; D065852:Spatial Memory / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects* / Q000473:pathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D054713:Bryostatins; D000076122:Disks Large Homolog 4 Protein; D020536:Enzyme Activators; D051860:Fragile X Messenger Ribonucleoprotein 1; D051528:Guanylate Kinases; D008565:Membrane Proteins; D051744:Protein Kinase C-epsilon; D064529:Receptor, Metabotropic Glutamate 5; D017661:Receptors, Presynaptic; C501447:Dlg4 protein, mouse; C578936:Grm5 protein, mouse; C046785:bryostatin 1