M₁ muscarinic acetylcholine receptors activate extracellular signal-regulated kinase in CA1 pyramidal neurons in mouse hippocampal slices

Activation of extracellular signal-regulated kinases (ERK) is crucial for many neural functions, including learning, memory, and synaptic plasticity. As muscarinic acetylcholine receptors (mAChR) modulate many of the same higher brain functions as ERK, we examined mAChR-mediated ERK activation in mouse hippocampal slices. The cholinergic agonist carbachol caused an atropine-sensitive ERK activation in the dendrites and somata CA1 pyramidal neurons. To determine the responsible mAChR subtype, we combined pharmacologic and genetic approaches. Pretreatment with M₁ antagonists inhibited ERK activation. Furthermore, mAChR-induced ERK activation was absent in slices from M₁ knockout mice. ERK activation was normal in slices derived from other mAChR subtype knockouts (M₂, M₃, and M₄), although these other subtypes are expressed in many of the same neurons. Thus, we demonstrate divergent functions for the different mAChR subtypes. We conclude that M₁ is responsible for mAChR-mediated ERK activation, providing a mechanism by which M₁ may modulate learning and memory.