Selective impairment of some forms of synaptic plasticity by oligomeric amyloid-β peptide in the mouse hippocampus: implication of extrasynaptic NMDA receptors.
Alzheimer's disease is characterized by the loss of memory and synaptic damage. Evidence is accumulating for a causal role of soluble oligomeric species of amyloid-β peptide (Aβo) in the impairment of synaptic plasticity and cognition but the precise mechanisms underlying these effects are still not clear. Synaptic plasticity such as long-term potentiation is thought to underlie learning and memory. While the effect of Aβ on long-term potentiation is well documented, a more general understanding of Aβ action on various aspects of plasticity involving synaptic and extrasynaptic receptors and the nature of the mechanisms involved in its effects are lacking. Using a combination of electrophysiological and biochemical techniques in mouse hippocampal slices, we show here that Aβo drastically affects synaptic plasticities induced by high stimulation frequencies through the involvement of extrasynaptic glutamate receptors. Experiments on hippocampal slices as well as on cultured cortical neurons show that Aβo potentiates extrasynaptic NMDA receptors-mediated responses. Pharmacological characterization indicates that GluN2B-containing NMDARs are involved in these responses. When synaptic and extrasynaptic glutamate receptor-mediated effects are dissociated using cortical neurons in culture, it appears that Aβo has differential effects on these two receptors types. We conclude that the pool of extrasynaptic GluN2B-containing NMDARs is a major target of Aβo in the hippocampus. During high frequency stimulation, Aβo dramatically impairs long-term neuronal responses.
Centre de Psychiatrie et de Neurosciences, UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Myriam
M
Kervern
Arnaud
A
Angeli
Olivier
O
Nicole
Frédéric
F
Léveillé
Bénédicte
B
Parent
Vincent
V
Villette
Alain
A
Buisson
Patrick
P
Dutar
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D003627:Data Interpretation, Statistical; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology*; D017774:Long-Term Potentiation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013569:Synapses / Q000187:drug effects*; D009435:Synaptic Transmission / Q000502:physiology
D016229:Amyloid beta-Peptides; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate