TY  - JOUR
AU  - Müller, Michaela Kerstin
AU  - Jacobi, Eric
AU  - Sakimura, Kenji
AU  - Malinow, Roberto
AU  - Engelhardt, Jakob
TI  - NMDA receptors mediate synaptic depression, but not spine loss in the dentate gyrus of adult amyloid Beta (Aβ) overexpressing mice.
JO  - Acta Neuropathologica Communications
VL  - 6
IS  - 1
SN  - 2051-5960
CY  - London
PB  - Biomed Central
M1  - DZNE-2020-06613
SP  - 110
PY  - 2018
AB  - 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.
KW  - Action Potentials: drug effects
KW  - Action Potentials: genetics
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: pathology
KW  - Amyloid beta-Peptides: chemistry
KW  - Amyloid beta-Peptides: genetics
KW  - Amyloid beta-Peptides: metabolism
KW  - Amyloid beta-Peptides: pharmacology
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Animals
KW  - Calcium-Calmodulin-Dependent Protein Kinase Type 2: genetics
KW  - Calcium-Calmodulin-Dependent Protein Kinase Type 2: metabolism
KW  - Dendritic Spines: pathology
KW  - Dentate Gyrus: cytology
KW  - Disease Models, Animal
KW  - Excitatory Amino Acid Agents: pharmacology
KW  - Excitatory Postsynaptic Potentials: drug effects
KW  - Excitatory Postsynaptic Potentials: genetics
KW  - Female
KW  - Gene Expression Regulation: drug effects
KW  - Gene Expression Regulation: genetics
KW  - HEK293 Cells
KW  - Humans
KW  - Male
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mice, Transgenic
KW  - Mutation: genetics
KW  - Neurons: drug effects
KW  - Neurons: physiology
KW  - Neurons: ultrastructure
KW  - Presenilin-1: genetics
KW  - Receptors, N-Methyl-D-Aspartate: genetics
KW  - Receptors, N-Methyl-D-Aspartate: metabolism
KW  - Synapses: drug effects
KW  - Synapses: physiology
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - Excitatory Amino Acid Agents (NLM Chemicals)
KW  - PSEN1 protein, human (NLM Chemicals)
KW  - Presenilin-1 (NLM Chemicals)
KW  - Receptors, N-Methyl-D-Aspartate (NLM Chemicals)
KW  - Calcium-Calmodulin-Dependent Protein Kinase Type 2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30352630
C2  - pmc:PMC6198500
DO  - DOI:10.1186/s40478-018-0611-4
UR  - https://pub.dzne.de/record/140291
ER  -