title: Bryostatin-1 restores hippocampal synapses and spatial learning and memory in adult fragile x mice.
abstract: Fragile X syndrome (FXS) is caused by transcriptional silencing in neurons of the FMR1 gene product, fragile X mental retardation protein (FMRP), a repressor of dendritic mRNA translation. The lack of FMRP leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, a disorder that currently has no effective therapeutics. Fragile X mice were treated with chronic bryostatin-1, a relatively selective protein kinase ε activator with pharmacological profiles of rapid mGluR desensitization, synaptogenesis, and synaptic maturation/repairing. Differences in the major FXS phenotypes, synapses, and cognitive functions were evaluated and compared among the age-matched groups. Long-term treatment with bryostatin-1 rescues adult fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in hippocampal brain-derived neurotrophic factor expression and secretion, postsynaptic density-95 levels, glycogen synthase kinase-3β phosphorylation, transformation of immature dendritic spines to mature synapses, densities of the presynaptic and postsynaptic membranes, and spatial learning and memory. Our results show that synaptic and cognitive function of adult FXS mice can be normalized through pharmacologic treatment and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation even after postpartum brain development has largely completed.
authors.affiliation: Blanchette Rockefeller Neurosciences Institute, Morgantown, West Virginia.
authors.forename: Miao-Kun
authors.initials: MK
authors.lastname: Sun
authors.forename: Jarin
authors.initials: J
authors.lastname: Hongpaisan
authors.forename: Chol Seung
authors.initials: CS
authors.lastname: Lim
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Alkon
mesh_terms: D000818:Animals; D054713:Bryostatins / Q000008:administration & dosage / Q000627:therapeutic use*; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D013037:Spatial Behavior / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure
chemical_list: D054713:Bryostatins; C046785:bryostatin 1; D051744:Protein Kinase C-epsilon