Facilitation of Long-Term Potentiation by Muscarinic M1 Receptors Is Mediated by Inhibition of SK Channels

Summary 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 M1 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 M1 receptors. N-methyl-D-aspartate receptor (NMDAR) opening during theta burst stimulation was enhanced by M1 receptor activation, indicating this is the mechanism for LTP facilitation. M1 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 M1 receptor activation inhibits SK channels, allowing enhanced NMDAR activity and leading to a facilitation of LTP induction in the hippocampus.

• Publication year

  2010

• Venue

  Neuron

• Publication date

  2010-12-09

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.neuron.2010.11.018PMID 21145007PMCID 3003154
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• M1 receptor-driven facilitation of N-methyl-D-aspartate receptor activation is mediated by inhibition of SK channels that would otherwise hyperpolarize postsynaptic spines.

  Confidence 0.97

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• M1 receptor activation enhances N-methyl-D-aspartate receptor opening during theta burst stimulation.

  Confidence 0.96

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• Acetylcholine release from cholinergic fibers also facilitates long-term potentiation through M1 receptor activation.

  Confidence 0.95

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• Activation of M1 receptors by 77-LH-28-1 facilitates theta-burst-induced long-term potentiation at Schaffer collateral synapses in the hippocampus.

  Confidence 0.98

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review

• 77-lh-28-1

  compound, agonist

  A highly selective allosteric agonist used to activate M1 receptors in the experiments.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• acetylcholine

  neurotransmitter

  The endogenous neurotransmitter released by cholinergic fibers in the preparation.

  Aliases: ACh

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• cholinergic fiber

  fiber, neural projection

  Neural fibers that release acetylcholine onto the hippocampal circuit examined here.

  Aliases: cholinergic fibers

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• hippocampus

  brain region

  A brain region containing the synapses used in the plasticity experiments.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• long-term potentiation

  synaptic plasticity, outcome

  A persistent increase in synaptic strength measured as the plasticity outcome in the hippocampal preparation.

  Aliases: LTP

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• m1 receptor

  receptor

  A muscarinic acetylcholine receptor subtype examined as the mediator of cholinergic effects in hippocampal plasticity.

  Aliases: muscarinic M1 receptor, M1 muscarinic receptor

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• n-methyl-d-aspartate receptor

  receptor, ion channel

  A glutamate receptor whose opening was assessed as part of the mechanism linking cholinergic signaling to plasticity.

  Aliases: NMDAR

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• schaffer collateral synapse

  synapse

  The hippocampal synaptic connection between Schaffer collateral inputs and CA1 pyramidal cells examined for plasticity.

  Aliases: Schaffer collateral synapses

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• sk channel

  ion channel

  A small-conductance calcium-activated potassium channel implicated in regulating postsynaptic spine excitability.

  Aliases: small-conductance Ca2+-activated K+ channel, SK channels

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• theta burst stimulation

  stimulation protocol

  A patterned electrical stimulation protocol used to induce synaptic plasticity at hippocampal synapses.

  Aliases: TBS

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review

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