Prolonged and specific spatial training during adolescence reverses adult hippocampal network impairments in a mouse model of fragile X syndrome

The Fragile X Syndrome (FXS) is the leading monogenetic cause of cognitive impairment and autism. A hallmark of FXS patients and the FXS mouse model (Fmr1 KO) is an overabundance of immature appearing dendritic spines in the cortex and hippocampus which is associated with behavioral deficits. Spine analysis in the different hippocampal subregions and at different developmental stages revealed that in adult mice, hippocampal spine pathology occurs specifically in the CA3 subregion, which plays a pivotal role in pattern completion processes important for efficient memory recall from parts of the initial memory stimulus. In line with this synaptic defect we document an impairment in memory recall during partially cued reference memory test in the Morris water maze task. This is accompanied by impaired recruitment of engram cells as well as impaired spine structural plasticity in the CA3 region. In order to promote hippocampal network development adolescent mice were either raised in an enriched environment or subjected to specific hippocampus-dependent spatial training. Intriguingly, only specific spatial training alleviated the cognitive symptoms and the spine phenotype shown in adult Fmr1 KO mice suggesting that specific stimulation of hippocampal networks during development might be used in the future as a therapeutic strategy. [Display omitted] •In the FXS mouse model reports about hippocampal synapse pathology are controversial.•Spine abnormalities in adult mice are restricted specifically to the CA3 subregion.•In line with this pattern completion processes during memory recall are impaired.•Prolonged spatial training as a potential therapeutic approach reverses network defects.