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Cell Rep. 2018 Oct 2;25(1):168-182.e6. doi: 10.1016/j.celrep.2018.09.028.

Activity-Dependent Netrin-1 Secretion Drives Synaptic Insertion of GluA1-Containing AMPA Receptors in the Hippocampus.

Author information

1
Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada; McGill Program in Neuroengineering, McGill University, Montreal, QC H3A 2B4, Canada.
2
CERVO Brain Research Center, 2601 de la Canardière, Quebec, QC G1J 2G3, Canada.
3
Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada; Department of Chemistry, McGill University, Montreal, QC H3A 0B8, Canada.
4
Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
5
McGill Program in Neuroengineering, McGill University, Montreal, QC H3A 2B4, Canada; Department of Chemistry, McGill University, Montreal, QC H3A 0B8, Canada; Department of Physics, McGill University, Montreal, QC H3A 2T8, Canada.
6
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC H3G 1Y6, Canada.
7
Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC H3A 0G1, Canada.
8
CERVO Brain Research Center, 2601 de la Canardière, Quebec, QC G1J 2G3, Canada; Department of Biochemistry, Microbiology and Bio-informatics, Université Laval, Quebec, QC G1K 7P4, Canada.
9
Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada; McGill Program in Neuroengineering, McGill University, Montreal, QC H3A 2B4, Canada. Electronic address: timothy.kennedy@mcgill.ca.

Abstract

Dynamic trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs) to synapses is critical for activity-dependent synaptic plasticity underlying learning and memory, but the identity of key molecular effectors remains elusive. Here, we demonstrate that membrane depolarization and N-methyl-D-aspartate receptor (NMDAR) activation triggers secretion of the chemotropic guidance cue netrin-1 from dendrites. Using selective genetic deletion, we show that netrin-1 expression by excitatory neurons is required for NMDAR-dependent long-term potentiation (LTP) in the adult hippocampus. Furthermore, we demonstrate that application of exogenous netrin-1 is sufficient to trigger the potentiation of excitatory glutamatergic transmission at hippocampal Schaffer collateral synapses via Ca2+-dependent recruitment of GluA1-containing AMPARs, promoting the maturation of immature or nascent synapses. These findings identify a central role for activity-dependent release of netrin-1 as a critical effector of synaptic plasticity in the adult hippocampus.

KEYWORDS:

AMPA receptor trafficking; CA1 pyramidal neurons; DCC; GluR1; axon guidance; deleted-in-colorectal cancer; long-term potentiation

PMID:
30282026
DOI:
10.1016/j.celrep.2018.09.028
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