Novel contribution of cell surface and intracellular M1-muscarinic acetylcholine receptors to synaptic plasticity in hippocampus

J Neurochem. 2013 Aug;126(3):360-71. doi: 10.1111/jnc.12306. Epub 2013 Jun 9.


Muscarinic acetylcholine receptors (mAChRs) are well known to transmit extracellular cholinergic signals into the cytoplasm from their position on the cell surface. However, we show here that M1-mAChRs are also highly expressed on intracellular membranes in neurons of the telencephalon and activate signaling cascades distinct from those of cell surface receptors, contributing uniquely to synaptic plasticity. Radioligand-binding experiments with cell-permeable and -impermeable ligands and immunohistochemical observations revealed intracellular and surface distributions of M1-mAChRs in the hippocampus and cortex of rats, mice, and humans, in contrast to the selective occurrence on the cell surface in other tissues. All intracellular muscarinic-binding sites were abolished in M1-mAChR-gene-knockout mice. Activation of cell surface M1-mAChRs in rat hippocampal neurons evoked phosphatidylinositol hydrolysis and network oscillations at theta rhythm, and transiently enhanced long-term potentiation. On the other hand, activation of intracellular M1-mAChRs phosphorylated extracellular-regulated kinase 1/2 and gradually enhanced long-term potentiation. Our data thus demonstrate that M1-mAChRs function at both surface and intracellular sites in telencephalon neurons including the hippocampus, suggesting a new mode of cholinergic transmission in the central nervous system.

Keywords: ERK1/2; LTP; M1-muscarinic receptor; cell surface and intracellular GPCR; synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Blotting, Western
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • Cytoplasm / chemistry
  • Cytoplasm / metabolism
  • Female
  • Hippocampus / metabolism*
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Neuronal Plasticity / physiology*
  • Neurons / metabolism
  • Patch-Clamp Techniques
  • Rats
  • Rats, Wistar
  • Receptor, Muscarinic M1 / metabolism*
  • Synapses / metabolism
  • Synaptic Transmission / physiology


  • Receptor, Muscarinic M1