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Acetylcholine synergizes with netrin-1 to drive persistent firing in the entorhinal cortex

View ORCID ProfileStephen D. Glasgow, View ORCID ProfileEdwin W. Wong, Ian V. Beamish, Kevin Lancon, View ORCID ProfileJulien Gibon, View ORCID ProfilePhilippe Séguéla, View ORCID ProfileEdward S. Ruthazer, View ORCID ProfileTimothy E. Kennedy
doi: https://doi.org/10.1101/2020.07.08.194274
Stephen D. Glasgow
1Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, H3A 2B4, Canada
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Edwin W. Wong
1Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, H3A 2B4, Canada
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Ian V. Beamish
1Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, H3A 2B4, Canada
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Kevin Lancon
1Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, H3A 2B4, Canada
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Julien Gibon
1Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, H3A 2B4, Canada
†Department of Biology, University of British Columbia, Kelowna, BC, V1V 1V7, Canada
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Philippe Séguéla
1Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, H3A 2B4, Canada
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Edward S. Ruthazer
1Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, H3A 2B4, Canada
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  • For correspondence: ed.ruthazer@mcgill.ca timothy.kennedy@mcgill.ca
Timothy E. Kennedy
1Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, H3A 2B4, Canada
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  • For correspondence: ed.ruthazer@mcgill.ca timothy.kennedy@mcgill.ca
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Abstract

The ability of the mammalian brain to maintain spatial representations of external or internal information for short periods of time has been associated with sustained neuronal spiking and reverberatory neural network activity in the medial entorhinal cortex. Here, we show that cholinergic activation of muscarinic receptors on entorhinal cortical neurons mediates plasma membrane recruitment of the netrin-1 receptor deleted-in-colorectal cancer (DCC) to promote muscarinic receptor-mediated persistent firing. Conditional deletion of netrin-1 or DCC, which are required for synaptic plasticity, inhibits cholinergic persistent firing, and leads to deficits in spatial working memory. Together, these findings indicate that normal working memory function requires synergistic action of acetylcholine and netrin-1.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 08, 2020.
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Acetylcholine synergizes with netrin-1 to drive persistent firing in the entorhinal cortex
Stephen D. Glasgow, Edwin W. Wong, Ian V. Beamish, Kevin Lancon, Julien Gibon, Philippe Séguéla, Edward S. Ruthazer, Timothy E. Kennedy
bioRxiv 2020.07.08.194274; doi: https://doi.org/10.1101/2020.07.08.194274
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Acetylcholine synergizes with netrin-1 to drive persistent firing in the entorhinal cortex
Stephen D. Glasgow, Edwin W. Wong, Ian V. Beamish, Kevin Lancon, Julien Gibon, Philippe Séguéla, Edward S. Ruthazer, Timothy E. Kennedy
bioRxiv 2020.07.08.194274; doi: https://doi.org/10.1101/2020.07.08.194274

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