Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aß in vivo.
Item Type:Journal Article
Citation:Klyubin I, Ondrejcak T, Hayes J, Cullen WK, Mably AJ, Walsh DM, Rowan MJ, Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aß in vivo., Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 369, 1633, 2014, 20130147
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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.
Author: ROWAN, MICHAEL
Type of material:Journal Article
Series/Report no:Philosophical transactions of the Royal Society of London. Series B, Biological sciences
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