Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits

Jon Palacios-Filardo, Matt Udakis, Jack R Mellor, et al.

Research output: Contribution to journalArticle (Academic Journal)peer-review

16 Citations (Scopus)
52 Downloads (Pure)

Abstract

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations. An influential but largely untested theory proposes that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory inhibitory balance and CA1 activation by entorhinal inputs. Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M3 and M4 receptors respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation.
Original languageEnglish
Article number5475
JournalNature Communications
Volume12
Issue number1
Early online date16 Sept 2021
DOIs
Publication statusPublished - Dec 2021

Bibliographical note

Funding Information:
We thank Paul Anastasiades and Paul Chadderton for critical input to previous versions of the manuscript and all members of the Mellor group for discussion. We also thank Dr Jürgen Wess (NIH, NIDDK) for providing the M3 receptor KO mice and Sosei Heptares for providing Compound 1. This work was supported by Wellcome Trust and Biotechnology and Biological Sciences Research Council (BBSRC).

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • acetylcholine
  • hippocampus
  • CA3
  • CA1
  • entorhinal cortex

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