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

• Published in: Nature communications Vol. 12; no. 1; p. 5475
• Main Authors: Palacios-Filardo, Jon, Udakis, Matt, Brown, Giles A., Tehan, Benjamin G., Congreve, Miles S., Nathan, Pradeep J., Brown, Alastair J. H., Mellor, Jack R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.09.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/378; 631/378/3920; 631/378/548; 631/378/87; 9/74; Acetylcholine - metabolism; Acetylcholine receptors (muscarinic); Animals; CA1 Region, Hippocampal - cytology; CA1 Region, Hippocampal - physiology; Carbachol - pharmacology; Cholinergic Agonists - pharmacology; Cholinergics; Cortex (entorhinal); Cortex (somatosensory); Entorhinal Cortex - cytology; Entorhinal Cortex - physiology; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - physiology; Feedback, Physiological - drug effects; Feedback, Physiological - physiology; Hippocampus; Humanities and Social Sciences; Interneurons - metabolism; Interneurons - physiology; Male; Memory; Mice; Mice, Inbred C57BL; Mice, Knockout; Modulation; multidisciplinary; Neurons; Patch-Clamp Techniques; Pyramidal Cells - metabolism; Pyramidal Cells - physiology; Receptor mechanisms; Receptor, Muscarinic M3 - genetics; Receptor, Muscarinic M3 - metabolism; Receptors; Representations; Science; Science (multidisciplinary); Subpopulations; Synaptic Transmission - drug effects; Synaptic Transmission - physiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25280-5

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 M 3 and M 4 receptors, respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation. In this study, acetylcholine release is shown to reorganise hippocampal CA1 inhibitory networks resulting in prioritisation of entorhinal input over CA3 input. This is achieved by activation of a combination of M3 and M4 muscarinic receptors.