Involvement of GluN2B subunit containing N-methyl-d-aspartate (NMDA) receptors in mediating the acute and chronic synaptotoxic effects of oligomeric amyloid-beta (Aβ) in murine models of Alzheimer's disease (AD).
To elucidate whether a permanent reduction of the GluN2B subunit affects the pathology of Alzheimer's disease (AD), we cross-bred mice heterozygous for GluN2B receptors in the forebrain (hetGluN2B) with a mouse model for AD carrying a mutated amyloid precursor protein with the Swedish and Arctic mutation (mAPP) resulting in a hetGluN2B/mAPP transgenic. By means of voltage-sensitive dye imaging (VSDI) in the di-synaptic hippocampal pathway and the recording of field excitatory postsynaptic potentials (fEPSPs), hippocampal slices of all genotypes (WT, hetGluN2B, mAPP and hetGluN2B/mAPP, age 9-18 months) were tested for spatiotemporal activity propagation and long-term potentiation (LTP) induction. CA1-LTP induced by high frequency stimulation (HFS; 100 Hz/1s) was not different in all genotypes. Aβ1-42(50 nM)-application reduced potentiation of fEPSP in WT and hetGluN2B/mAPP mice, LTP in mAPP and hetGluN2B mice was not affected. For VSDI a fast depolarization signal was evoked in the granule cell layer and propagation was analysed in hippocampal CA3 and CA1 region before and after theta stimulation (100pulses/5 Hz). LTP was not significantly different between all genotypes. In mAPP mice θ-stim produced an epileptiform activity reflected in a pronounced prolongation of the FDS compared to the other genotypes. In slices of hetGluN2B/mAPP and GluN2B mice, however, these parameters were similar to WT mice indicating a reversal effect of the attenuated GluN2B expression. The induction of a hetGluN2B mutation in the mAPP reversed some pathophysiological changes on hippocampal LTP and provide further evidence for the involvement of the glutamatergic system in AD and emphasize the GluN2B subunit as a potential target for AD treatment.
Department of Anaesthesiology, Technische Universität München, Munich, Germany; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany. Electronic address: g.rammes@tum.de.
Gerhard
G
Rammes
Department of Anaesthesiology, Technische Universität München, Munich, Germany.
Corinna
C
Mattusch
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Matthias
M
Wulff
Department of Anaesthesiology, Technische Universität München, Munich, Germany.
Franziska
F
Seeser
Department of Anaesthesiology, Technische Universität München, Munich, Germany.
Matthias
M
Kreuzer
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Kaichuan
K
Zhu
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Jan M
JM
Deussing
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Jochen
J
Herms
Non-Clinical Science, Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany.
Chris G
CG
Parsons
D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D046509:Tissue Culture Techniques
D000682:Amyloid; D016229:Amyloid beta-Peptides; C121001:NR2B NMDA receptor; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; C075222:amyloid beta-protein (1-42)
Alzheimer; Amyloid beta; GluN2B; Hippocampus; In vitro; LTP; VSDI