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

Jon Palacios-Filardo, Matt Udakis, Giles A. Brown, Benjamin G. Tehan, Miles S. Congreve, Pradeep J. Nathan, Alastair J.H. Brown, Jack R. Mellor

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Feb 10, 2020
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Received Date: 16th January 20

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations by facilitating synaptic plasticity. It is also proposed 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, but this influential theory has not been directly tested. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, greater depression of feedforward inhibition from entorhinal cortex results in an overall enhancement of excitatory-inhibitory balance and CA1 activation. Underpinning the prioritisation of entorhinal inputs, entorhinal and CA3 pathways engage distinct feedforward interneuron subpopulations and depression is mediated differentially by presynaptic muscarinic M3 and M4 receptors respectively. These mechanisms enable acetylcholine to prioritise novel information inputs to CA1 during memory formation and suggest selective muscarinic targets for therapeutic intervention.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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