Early neuronal dysfunction by amyloid β oligomers depends on activation of NR2B-containing NMDA receptors.
Several studies indicate that NMDA receptor signaling is involved in Aβ oligomer-mediated impairment of neuronal function and morphology. Utilizing primary neuronal cell culture and hippocampal slices from rat and mouse, we found that Aβ oligomer administration readily impairs long-term potentiation, reduces baseline synaptic transmission, decreases neuronal spontaneous network activity and induces retraction of synaptic contacts long before major cytotoxic effects are visible. Interestingly, all these effects can be blocked with the NR2B-containing NMDA-receptor antagonist ifenprodil or Ro 25-6981 suggesting that activation of downstream effectors of these receptors is involved in early detrimental actions of Aβ oligomers. In line we found that Jacob, a messenger that can couple extrasynaptic NMDA-receptor activity to CREB dephosphorylation, accumulates in the nucleus after Aβ oligomer administration and that the nuclear accumulation of Jacob can be blocked by a simultaneous application of ifenprodil. We conclude that Aβ oligomers induce early neuronal dysfunction mainly by activation of NR2B-containing NMDA-receptors.
Project Group Neuropharmacology, Leibniz Institute for Neurobiology, Brenneckestrasse 6, 39118 Magdeburg, Germany.
Raik
R
Rönicke
Marina
M
Mikhaylova
Sabine
S
Rönicke
Jessica
J
Meinhardt
Ulrich H
UH
Schröder
Marcus
M
Fändrich
Georg
G
Reiser
Michael R
MR
Kreutz
Klaus G
KG
Reymann
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016229:Amyloid beta-Peptides; C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C010739:ifenprodil