Journal
NEURON
Volume 68, Issue 5, Pages 948-963Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2010.11.018
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Funding
- GlaxoSmithKline
- Marie Curie fellowship
- Biotechnology and Biological Sciences Research Council (BBSRC)
- Belgian Science Policy Interuniversity Attraction Poles (IAP) programme
- Medical Research Council
- Wellcome Trust
- European Union Network of European Neuroscience Institutes (ENI-NET)
- Medical Research Council [G120/838] Funding Source: researchfish
- MRC [G120/838] Funding Source: UKRI
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Muscarinic receptor activation facilitates the induction of synaptic plasticity and enhances cognitive function. However, the specific muscarinic receptor subtype involved and the critical intracellular signaling pathways engaged have remained controversial. Here, we show that the recently discovered highly selective allosteric M-1 receptor agonist 77-LH-28-1 facilitates long-term potentiation (LTP) induced by theta burst stimulation at Schaffer collateral synapses in the hippocampus. Similarly, release of acetylcholine by stimulation of cholinergic fibers facilitates LTP via activation of M-1 receptors. N-methyl-D-aspartate receptor (NMDAR) opening during theta burst stimulation was enhanced by M-1 receptor activation, indicating this is the mechanism for LIP facilitation. M-1 receptors were found to enhance NMDAR activation by inhibiting SK channels that otherwise act to hyperpolarize postsynaptic spines and inhibit NMDAR opening. Thus, we describe a mechanism where M-1 receptor activation inhibits SK channels, allowing enhanced NMDAR activity and leading to a facilitation of LIP induction in the hippocampus.
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