Abstract
Key points: Fragile X syndrome (FXS) is a genetic condition that is the most common form of inherited intellectual impairment and causes a range of neurodevelopmental complications including learning disabilities and intellectual disability and shares many characteristics with autism spectrum disorder (ASD). In the FXS mouse model, Fmr1-/y , impaired synaptic plasticity was restored by pharmacologically inhibiting GluN2A-containing NMDA receptors but not GluN2B-containing receptors. Similar results were obtained by crossing Fmr1-/y with GluN2A knock-out (Grin2A-/- ) mice. These results suggest that dampening the elevated levels of GluN2A-containing NMDA receptors in Fmr1-/y mice has the potential to restore hyperexcitability of the neural circuitry to (a more) normal-like level of brain activity. NMDA receptors (NMDARs) play important roles in synaptic plasticity at central excitatory synapses, and dysregulation of their function may lead to severe disorders such Fragile X syndrome (FXS). FXS is caused by transcriptional silencing of the FMR1 gene followed by lack of the encoding protein. Here we examined the effects of pharmacological and genetic manipulation of hippocampal NMDAR functions in long-term potentiation (LTP) and depression (LTD). We found impaired NMDAR-dependent LTP in the Fmr1-deficient mice, which could be fully restored when GluN2A-containing NMDARs was pharmacological inhibited. Interestingly, similar LTP effects were observed when the GluN2A gene (Grin2a) was deleted in Fmr1-/y mice (Fmr1-/y /Grin2a-/- double knockout). In addition, GluN2A inhibition improved elevated mGluR5-dependent LTD to normal level in the Fmr1-/y mouse. These findings suggest that GluN2A is a promising target in FXS research that could help us better understand the disorder.