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@ARTICLE{Mller:140291,
      author       = {Müller, Michaela Kerstin and Jacobi, Eric and Sakimura,
                      Kenji and Malinow, Roberto and Engelhardt, Jakob},
      title        = {{NMDA} receptors mediate synaptic depression, but not spine
                      loss in the dentate gyrus of adult amyloid {B}eta ({A}β)
                      overexpressing mice.},
      journal      = {Acta Neuropathologica Communications},
      volume       = {6},
      number       = {1},
      issn         = {2051-5960},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2020-06613},
      pages        = {110},
      year         = {2018},
      abstract     = {Amyloid beta (Aβ)-mediated synapse dysfunction and spine
                      loss are considered to be early events in Alzheimer's
                      disease (AD) pathogenesis. N-methyl-D-aspartate receptors
                      (NMDARs) have previously been suggested to play a role for
                      Amyloid beta (Aβ) toxicity. Pharmacological block of NMDAR
                      subunits in cultured neurons and mice suggested that NMDARs
                      containing the GluN2B subunit are necessary for Aβ-mediated
                      changes in synapse number and function in hippocampal
                      neurons. Interestingly, NMDARs undergo a developmental
                      switch from GluN2B- to GluN2A-containing receptors. This
                      indicates different functional roles of NMDARs in young mice
                      compared to older animals. In addition, the lack of
                      pharmacological tools to efficiently dissect the role of
                      NMDARs containing the different subunits complicates the
                      interpretation of their specific role. In order to address
                      this problem and to investigate the specific role for Aβ
                      toxicity of the distinct NMDAR subunits in dentate gyrus
                      granule cells of adult mice, we used conditional knockout
                      mouse lines for the subunits GluN1, GluN2A and GluN2B.
                      Aβ-mediated changes in synaptic function and neuronal
                      anatomy were investigated in several-months old mice with
                      virus-mediated overproduction of Aβ and in 1-year old 5xFAD
                      mice. We found that all three NMDAR subunits contribute to
                      the Aβ-mediated decrease in the number of functional
                      synapses. However, NMDARs are not required for the spine
                      number reduction in dentate gyrus granule cells after
                      chronic Aβ-overproduction in 5xFAD mice. Furthermore, the
                      amplitude of synaptic and extrasynaptic NMDAR-mediated
                      currents was reduced in dentate gyrus granule of 5xFAD mice
                      without changes in current kinetics, suggesting that a
                      redistribution or change in subunit composition of NMDARs
                      does not play a role in mediating Amyloid beta (Aβ)
                      toxicity. Our study indicates that NMDARs are involved in AD
                      pathogenesis by compromising synapse function but not by
                      affecting neuron morphology.},
      keywords     = {Action Potentials: drug effects / Action Potentials:
                      genetics / Alzheimer Disease: genetics / Alzheimer Disease:
                      pathology / Amyloid beta-Peptides: chemistry / Amyloid
                      beta-Peptides: genetics / Amyloid beta-Peptides: metabolism
                      / Amyloid beta-Peptides: pharmacology / Amyloid beta-Protein
                      Precursor: genetics / Animals / Calcium-Calmodulin-Dependent
                      Protein Kinase Type 2: genetics /
                      Calcium-Calmodulin-Dependent Protein Kinase Type 2:
                      metabolism / Dendritic Spines: pathology / Dentate Gyrus:
                      cytology / Disease Models, Animal / Excitatory Amino Acid
                      Agents: pharmacology / Excitatory Postsynaptic Potentials:
                      drug effects / Excitatory Postsynaptic Potentials: genetics
                      / Female / Gene Expression Regulation: drug effects / Gene
                      Expression Regulation: genetics / HEK293 Cells / Humans /
                      Male / Mice / Mice, Inbred C57BL / Mice, Transgenic /
                      Mutation: genetics / Neurons: drug effects / Neurons:
                      physiology / Neurons: ultrastructure / Presenilin-1:
                      genetics / Receptors, N-Methyl-D-Aspartate: genetics /
                      Receptors, N-Methyl-D-Aspartate: metabolism / Synapses: drug
                      effects / Synapses: physiology / Amyloid beta-Peptides (NLM
                      Chemicals) / Amyloid beta-Protein Precursor (NLM Chemicals)
                      / Excitatory Amino Acid Agents (NLM Chemicals) / PSEN1
                      protein, human (NLM Chemicals) / Presenilin-1 (NLM
                      Chemicals) / Receptors, N-Methyl-D-Aspartate (NLM Chemicals)
                      / Calcium-Calmodulin-Dependent Protein Kinase Type 2 (NLM
                      Chemicals)},
      cin          = {AG Engelhardt},
      ddc          = {610},
      cid          = {I:(DE-2719)1013023},
      pnm          = {341 - Molecular Signaling (POF3-341)},
      pid          = {G:(DE-HGF)POF3-341},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30352630},
      pmc          = {pmc:PMC6198500},
      doi          = {10.1186/s40478-018-0611-4},
      url          = {https://pub.dzne.de/record/140291},
}