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.Fmr1 KO | hippocampus | object location memory | massed training | novel object recognition F ragile X syndrome (FXS) is the most common cause of inherited intellectual disability (ID) (1). Currently no treatments exist for cognitive deficits associated with FXS or other neurodevelopmental disorders with ID. Research on the fragile X mental retardation 1 (Fmr1) KO mouse model of FXS has identified impairments in synaptic signaling required to produce lasting synaptic modifications (2-6) with corresponding disturbances in the activation threshold and stabilization of hippocampal long-term potentiation (LTP) (7,8). These findings suggest specific synaptic disturbances underlie learning problems in FXS as well as targets for therapeutic interventions to improve cognitive function.The present experiments tested predictions from LTP studies as to how modified training paradigms might rescue synaptic signaling and learning in Fmr1 KO mice. There is a deep literature demonstrating that individuals learn better when trained in short trials spaced in time than in a single, extended training episode (9). We recently found that LTP exhibits a synaptic analog for this "spaced trials effect" (10). Specifically, in hippocampal field CA1 short trains of theta burst afferent stimulation spaced by 60 min elicit far greater synaptic potentiation than can be achieved with long theta trains or by repeated trains applied at shorter intervals. As LTP is considered a mechanism of memory encoding, we propose that spaced training regimens that use the same 60-min periodicity should facilitate hippocampus...

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