Cholinergic afferent stimulation induces axonal function plasticity in adult hippocampal granule cells

Neuron. 2015 Jan 21;85(2):346-63. doi: 10.1016/j.neuron.2014.12.030. Epub 2015 Jan 8.


Acetylcholine critically influences hippocampal-dependent learning. Cholinergic fibers innervate hippocampal neuron axons, dendrites, and somata. The effects of acetylcholine on axonal information processing, though, remain unknown. By stimulating cholinergic fibers and making electrophysiological recordings from hippocampal dentate gyrus granule cells, we show that synaptically released acetylcholine preferentially lowered the action potential threshold, enhancing intrinsic excitability and synaptic potential-spike coupling. These effects persisted for at least 30 min after the stimulation paradigm and were due to muscarinic receptor activation. This caused sustained elevation of axonal intracellular Ca(2+) via T-type Ca(2+) channels, as indicated by two-photon imaging. The enhanced Ca(2+) levels inhibited an axonal KV7/M current, decreasing the spike threshold. In support, immunohistochemistry revealed muscarinic M1 receptor, CaV3.2, and KV7.2/7.3 subunit localization in granule cell axons. Since alterations in axonal signaling affect neuronal firing patterns and neurotransmitter release, this is an unreported cellular mechanism by which acetylcholine might, at least partly, enhance cognitive processing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism*
  • Action Potentials / physiology*
  • Animals
  • Axons / metabolism*
  • Calcium / metabolism
  • Calcium Channels, T-Type / metabolism
  • Cholinergic Fibers / metabolism*
  • Dentate Gyrus / cytology
  • Dentate Gyrus / metabolism
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • KCNQ2 Potassium Channel / metabolism
  • KCNQ3 Potassium Channel / metabolism
  • Mice
  • Mossy Fibers, Hippocampal / metabolism*
  • Neuronal Plasticity
  • Neurons / metabolism
  • Neurons, Afferent / metabolism*
  • Potassium / metabolism
  • Receptor, Muscarinic M1 / metabolism*
  • Receptors, Muscarinic / metabolism
  • Synaptic Potentials / physiology*
  • Synaptic Transmission


  • Cacna1h protein, mouse
  • Calcium Channels, T-Type
  • KCNQ2 Potassium Channel
  • KCNQ3 Potassium Channel
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic
  • Acetylcholine
  • Potassium
  • Calcium