Rescue of NMDAR-Dependent synaptic plasticity in Fmr1 knock-out mice. Cereb. Cortex 25, 271--279. doi: 10.1093/cercor/ bht237

Fragile X Syndrome (FXS) is the most common form of inherited intel-lectual disability and results from a loss of Fragile X mental retar-dation protein (FMRP). FMRP is important for mRNA shuttling and translational control and binds to proteins important for synaptic plasticity. Like many developmental disorders, FXS is associated with alterations in synaptic plasticity that may impair learning and memory processes in the brain. However, it remains unclear whether FMRP plays a ubiquitous role in synaptic plasticity in all brain regions. We report that a loss of FMRP leads to impairments in N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plas-ticity in the dentate gyrus (DG), but not in the cornu ammonis area 1 (CA1) subregion of the hippocampus of adult mice. DG-specific defi-cits are accompanied by a significant reduction in NMDAR GluN1, GluN2A, and GluN2B subunit levels and reduced serine 831 GluA1 phosphorylation specifically in this region. Importantly, we demon-strate that treatment with NMDAR co-agonists (glycine or D-serine) independently rescue impairments in NMDAR-dependent synaptic plasticity in the DG of the Fragile X mental retardation 1 (Fmr1) knockout mouse. These findings implicate the NMDAR in the patho-physiology of FXS and suggest that indirect agonists of the NMDAR may be a successful therapeutic intervention in FXS