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

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

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UCL School of Pharmacy, University College London, London, WC1N 1AX, UK.
Departamento de Ciencias Medicas, Universidad de Castilla-La Mancha, 02006 Albacete, Spain.
Neurology and Neuroscience, Baylor College of Medicine, TX 77030, USA.
Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, UK.
UCL School of Pharmacy, University College London, London, WC1N 1AX, UK. Electronic address:


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.

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