RT Journal Article
SR Electronic
T1 Rescue of Synaptic Phenotypes and Spatial Memory in Young Fragile X Mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.115.231100
DO 10.1124/jpet.115.231100
A1 Miao-Kun Sun
A1 Jarin Hongpaisan
A1 Daniel L. Alkon
YR 2016
UL http://jpet.aspetjournals.org/content/early/2016/03/03/jpet.115.231100.abstract
AB Fragile X syndrome (FXS) is characterized by synaptic immaturity, cognitive impairment, and behavioral changes. The disorder is caused by transcriptional shutdown in neurons of the FMR1 gene product, fragile X mental retardation protein (FMRP). FMRP 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, a disorder which currently has no effective therapeutics. Here, young fragile X mice were treated with chronic bryostatin-1, a relatively selective PKCϵ activator, 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 (BDNF) expression, 2) the PSD-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 down-regulation of mGluR5 in the hippocampus and are more dramatic than those of a late-onset treatment in adult fragile X mice. The 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 down-regulation 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.