Facilitation of Long-Term Potentiation by Muscarinic M sub(1) Receptors Is Mediated by Inhibition of SK Channels

• Published in: Neuron (Cambridge, Mass.) Vol. 68; no. 5; pp. 948 - 963
• Main Authors: Buchanan, Katherine A, Petrovic, Milos M, Chamberlain, Sophie EL, Marrion, Neil V, Mellor, Jack R
• Format: Journal Article
• Language: English
• Published: 09.12.2010
• ISSN: 0896-6273
• DOI: 10.1016/j.neuron.2010.11.018

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 sub(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 sub(1) receptors. N-methyl-D-aspartate receptor (NMDAR) opening during theta burst stimulation was enhanced by M sub(1) receptor activation, indicating this is the mechanism for LTP facilitation. M sub(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 sub(1) receptor activation inhibits SK channels, allowing enhanced NMDAR activity and leading to a facilitation of LTP induction in the hippocampus. Highlights: The muscarinic M1 receptor allosteric agonist 77-LH-28-1 facilitates LTP induction M1 receptor activation inhibits SK channel function Inhibition of SK channels enhances NMDA receptor opening during LTP induction PKC mediates the inhibition of SK channels by M1 receptors