Acetylcholine synergizes with netrin-1 to drive persistent firing in the entorhinal cortex
Stephen D. Glasgow,
Teddy A.J. Fisher,
Edwin W. Wong,
Kevin Lançon,
Kira M. Feighan,
Ian V. Beamish,
Julien Gibon,
Philippe Séguéla,
Edward S. Ruthazer,
Timothy E. Kennedy
Affiliations
Stephen D. Glasgow
Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC H3A 2B4, Canada
Teddy A.J. Fisher
Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC H3A 2B4, Canada
Edwin W. Wong
Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC H3A 2B4, Canada
Kevin Lançon
Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC H3A 2B4, Canada
Kira M. Feighan
Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC H3A 2B4, Canada
Ian V. Beamish
Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC H3A 2B4, Canada
Julien Gibon
Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC H3A 2B4, Canada
Philippe Séguéla
Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC H3A 2B4, Canada
Edward S. Ruthazer
Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Corresponding author
Timothy E. Kennedy
Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Corresponding author
Summary: 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 conditional genetic deletion of netrin-1 or the netrin receptor deleted-in-colorectal cancer (DCC) from forebrain excitatory neurons leads to deficits in short-term spatial memory. We then demonstrate that conditional deletion of either netrin-1 or DCC inhibits cholinergic persistent firing and show that cholinergic activation of muscarinic receptors expressed by entorhinal cortical neurons promotes persistent firing by recruiting DCC to the plasma membrane. Together, these findings indicate that normal short-term spatial memory function requires the synergistic actions of acetylcholine and netrin-1.
