title: Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aβ in vivo.
abstract: Many endogenous factors influence the time course and extent of the detrimental effects of amyloid β-protein (Aβ) on synaptic function. Here, we assessed the impact of varying endogenous glutamatergic and cholinergic transmission by pharmacological means on the disruption of plasticity at hippocampal CA3-to-CA1 synapses in the anaesthetized rat. NMDA receptors (NMDARs) are considered critical in mediating Aβ-induced inhibition of long-term potentiation (LTP). However, intracerebroventricular injection of Aβ1-42 inhibited not only NMDAR-dependent LTP but also voltage-activated Ca(2+)-dependent LTP induced by strong conditioning stimulation during NMDAR blockade. On the other hand, another form of NMDAR-independent synaptic plasticity, endogenous acetylcholine-induced muscarinic receptor-dependent long-term enhancement, was not hindered by Aβ1-42. Interestingly, augmenting endogenous acetylcholine activation of nicotinic receptors prior to the injection of Aβ1-42 prevented the inhibition of NMDAR-dependent LTP, whereas the same intervention when introduced after the infusion of Aβ was ineffective. We also examined the duration of action of Aβ, including water soluble Aβ from Alzheimer's disease (AD) brain. Remarkably, the inhibition of LTP induction caused by a single injection of sodium dodecyl sulfate-stable Aβ dimer-containing AD brain extract persisted for at least a week. These findings highlight the need to increase our understanding of non-NMDAR mechanisms and of developing novel means of overcoming, rather than just preventing, the deleterious synaptic actions of Aβ.
authors.affiliation: Department of Pharmacology and Therapeutics, Institute of Neuroscience, Trinity College, , Biotechnology Building, Dublin 2, Republic of Ireland.
authors.forename: Igor
authors.initials: I
authors.lastname: Klyubin
authors.forename: Tomas
authors.initials: T
authors.lastname: Ondrejcak
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hayes
authors.forename: William K
authors.initials: WK
authors.lastname: Cullen
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Mably
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rowan
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001923:Brain Chemistry; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D045604:Extracellular Fluid / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; C075222:amyloid beta-protein (1-42); D000109:Acetylcholine
keywords: Alzheimer's disease; NMDA receptor; amyloid-β protein; long-term potentiation; muscarinic receptor; nicotinic receptor