Acetylcholine boosts dendritic NMDA spikes in a CA3 pyramidal neuron model

Rachel Humphries, Jack Mellor, Cian O'Donnell

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Acetylcholine has been proposed to facilitate the formation of memory ensembles within the hippocampal CA3 network, by enhancing plasticity at CA3-CA3 recurrent synapses. Regenerative NMDA receptor (NMDAR) activation in CA3 neuron dendrites (NMDA spikes) increase synaptic Ca influx and can trigger this synaptic plasticity. Acetylcholine inhibits potassium channels which enhances dendritic excitability and therefore could facilitate NMDA spike generation. Here, we investigate NMDAR-mediated nonlinear synaptic integration in stratum radiatum (SR) and stratum lacunosum moleculare (SLM) dendrites in a reconstructed CA3 neuron computational model and study the effect of cholinergic inhibition of potassium conductances on this nonlinearity. We found that distal SLM dendrites, with a higher input resistance, had a lower threshold for NMDA spike generation compared to SR dendrites. Simulating acetylcholine by blocking potassium channels (M-type, A-type, Ca -activated, and inwardly-rectifying) increased dendritic excitability and reduced the number of synapses required to generate NMDA spikes, particularly in the SR dendrites. The magnitude of this effect was heterogeneous across different dendritic branches within the same neuron. These results predict that acetylcholine facilitates dendritic integration and NMDA spike generation in selected CA3 dendrites which could strengthen connections between specific CA3 neurons to form memory ensembles. [Abstract copyright: Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.]
Original languageEnglish
Early online date12 Nov 2021
Publication statusPublished online - 12 Nov 2021

Bibliographical note

Funding Information:
We thank Simonas Griesius and Rahul Gupta for helpful discussions. This work was supported by Wellcome Trust (RH PhD studentship, JRM 101029/Z/13/Z ), BBSRC (JRM, BB/R002177/1 ), MRC (COD, MR/S026630/1 ), and Leverhulme Trust (COD, RPG-2019-229 ).

Publisher Copyright:
© 2021 IBRO


  • CA3
  • NMDA receptors
  • computational modelling
  • dendritic spikes
  • hippocampus
  • synaptic plasticity


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