Journal Article

DZNE-2020-06613

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png NMDA receptors mediate synaptic depression, but not spine loss in the dentate gyrus of adult amyloid Beta (Aβ) overexpressing mice.

Müller, M. K. ; Jacobi, E. ; Sakimura, K. ; Malinow, R. ; Engelhardt, J. (Last author)DZNE*

2018
Biomed Central London

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Please use a persistent id in citations: doi:10.1186/s40478-018-0611-4

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.

Keyword(s): Action Potentials: drug effects (MeSH) ; Action Potentials: genetics (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Amyloid beta-Peptides: chemistry (MeSH) ; Amyloid beta-Peptides: genetics (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Amyloid beta-Peptides: pharmacology (MeSH) ; Amyloid beta-Protein Precursor: genetics (MeSH) ; Animals (MeSH) ; Calcium-Calmodulin-Dependent Protein Kinase Type 2: genetics (MeSH) ; Calcium-Calmodulin-Dependent Protein Kinase Type 2: metabolism (MeSH) ; Dendritic Spines: pathology (MeSH) ; Dentate Gyrus: cytology (MeSH) ; Disease Models, Animal (MeSH) ; Excitatory Amino Acid Agents: pharmacology (MeSH) ; Excitatory Postsynaptic Potentials: drug effects (MeSH) ; Excitatory Postsynaptic Potentials: genetics (MeSH) ; Female (MeSH) ; Gene Expression Regulation: drug effects (MeSH) ; Gene Expression Regulation: genetics (MeSH) ; HEK293 Cells (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mice, Transgenic (MeSH) ; Mutation: genetics (MeSH) ; Neurons: drug effects (MeSH) ; Neurons: physiology (MeSH) ; Neurons: ultrastructure (MeSH) ; Presenilin-1: genetics (MeSH) ; Receptors, N-Methyl-D-Aspartate: genetics (MeSH) ; Receptors, N-Methyl-D-Aspartate: metabolism (MeSH) ; Synapses: drug effects (MeSH) ; Synapses: physiology (MeSH) ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Excitatory Amino Acid Agents ; PSEN1 protein, human ; Presenilin-1 ; Receptors, N-Methyl-D-Aspartate ; Calcium-Calmodulin-Dependent Protein Kinase Type 2

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Contributing Institute(s):

1. Synaptic Signalling and Neurodegeneration (AG Engelhardt)

Research Program(s):

1. 341 - Molecular Signaling (POF3-341) (POF3-341)

Appears in the scientific report 2018

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Database coverage:
; ; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Ebsco Academic Search ; IF >= 5 ; JCR ; SCOPUS ; Web of Science Core Collection

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