Facilitation of Long-Term Potentiation by Muscarinic M1 Receptors is mediated by inhibition of SK channels

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.