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Updated: May 8, 2026
Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation
Published on: July 6, 2022
Rescue of NMDAR-dependent synaptic plasticity in Fmr1 knock-out mice
C A Bostrom1, N-M Majaess2, K Morch2
1Division of Medical Sciences Department of Biology and.
Abstract:
Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and results from a loss of Fragile X mental retardation 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 plasticity in the dentate gyrus (DG), but not in the cornu ammonis area 1 (CA1) subregion of the hippocampus of adult mice. DG-specific deficits 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 demonstrate 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 pathophysiology of FXS and suggest that indirect agonists of the NMDAR may be a successful therapeutic intervention in FXS.
Insights
Fragile X Syndrome (FXS) involves intellectual disability due to loss of Fragile X mental retardation protein (FMRP). NMDAR co-agonist treatment rescues synaptic plasticity deficits in the dentate gyrus, suggesting a therapeutic avenue.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Fragile X Syndrome (FXS), the leading inherited intellectual disability, stems from the absence of Fragile X mental retardation protein (FMRP).
- FMRP is crucial for mRNA transport and translation, impacting synaptic plasticity and potentially learning and memory.
- The role of FMRP in synaptic plasticity across different brain regions remains incompletely understood.
Purpose of the Study:
- To investigate the role of FMRP in N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in distinct hippocampal subregions.
- To determine if FMRP loss affects NMDAR subunit expression and function in the hippocampus.
- To explore the therapeutic potential of NMDAR co-agonists in ameliorating FXS-related synaptic deficits.
Main Methods:
- Utilized the Fragile X mental retardation 1 (Fmr1) knockout mouse model.
- Assessed NMDAR-dependent synaptic plasticity in the dentate gyrus (DG) and cornu ammonis area 1 (CA1) of the hippocampus.
- Quantified NMDAR subunit levels (GluN1, GluN2A, GluN2B) and GluA1 phosphorylation (serine 831).
- Administered NMDAR co-agonists (glycine or D-serine) to evaluate rescue effects.
Main Results:
- Loss of FMRP impaired NMDAR-dependent synaptic plasticity specifically in the DG, not the CA1 region.
- DG-specific deficits correlated with reduced NMDAR GluN1, GluN2A, GluN2B subunit levels and serine 831 GluA1 phosphorylation.
- Treatment with glycine or D-serine successfully rescued the synaptic plasticity impairments in the DG of Fmr1 knockout mice.
Conclusions:
- FMRP plays a critical, region-specific role in NMDAR-dependent synaptic plasticity within the hippocampus.
- NMDAR dysfunction is implicated in the pathophysiology of Fragile X Syndrome.
- Targeting NMDARs with co-agonists presents a promising therapeutic strategy for FXS.
