title: Rescue of NMDAR-dependent synaptic plasticity in Fmr1 knock-out mice.
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.
authors: Division of Medical Sciences Department of Biology and.
authors: C A
authors: CA
authors: Bostrom
authors: Division of Medical Sciences Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada V8P 5C2.
authors: N-M
authors: NM
authors: Majaess
authors: Division of Medical Sciences Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada V8P 5C2.
authors: K
authors: K
authors: Morch
authors: Division of Medical Sciences Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada V8P 5C2.
authors: E
authors: E
authors: White
authors: Division of Medical Sciences Department of Biology and.
authors: B D
authors: BD
authors: Eadie
authors: Division of Medical Sciences.
authors: B R
authors: BR
authors: Christie
mesh_terms: D000818:Animals; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism; D005998:Glycine / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism*; D012694:Serine / Q000494:pharmacology
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D005998:Glycine; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; C497684:Fmr1 protein, mouse; C121673:Gprin1 protein, mouse; C121001:NR2B NMDA receptor
keywords: Fmr1 KO; Fragile X Syndrome; LTP; NMDAR; hippocampus