Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice

Significance There are no treatments for congenital intellectual disabilities. Here we show that newly discovered timing rules for maximizing hippocampal long-term potentiation predict training regimens that offset defects in synaptic chemistry and memory in the fragile X mental retardation 1 (Fmr1) KO model of fragile X syndrome. Wild-type mice required far less training to form stable memories when given three training trials separated by 1 hour as opposed to one extended session; shorter or longer intervals were ineffective. The same spaced training protocol rescued memory in Fmr1 KO mice and restored activation of synaptic ERK1/2, a kinase critical for both LTP and learning. These results suggest a readily implementable, neurobiologically based therapeutic strategy for a prevalent form of intellectual disability. Recent studies have shown that short, spaced trains of afferent stimulation produce much greater long-term potentiation (LTP) than that obtained with a single, prolonged stimulation episode. The present studies demonstrate that spaced training regimens, based on these LTP timing rules, facilitate learning in wild-type (WT) mice and can offset learning and synaptic signaling impairments in the fragile X mental retardation 1 (Fmr1) knockout (KO) model of fragile X syndrome. We determined that 5 min of continuous training supports object location memory (OLM) in WT but not Fmr1 KO mice. However, the same amount of training distributed across three short trials, spaced by one hour, produced robust long-term memory in the KOs. At least three training trials were needed to realize the benefit of spacing, and intertrial intervals shorter or longer than 60 min were ineffective. Multiple short training trials also rescued novel object recognition in Fmr1 KOs. The spacing effect was surprisingly potent: just 1 min of OLM training, distributed across three trials, supported robust memory in both genotypes. Spacing also rescued training-induced activation of synaptic ERK1/2 in dorsal hippocampus of Fmr1 KO mice. These results show that a spaced training regimen designed to maximize synaptic potentiation facilitates recognition memory in WT mice and can offset synaptic signaling and memory impairments in a model of congenital intellectual disability.