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

• Published in: Cell reports (Cambridge) Vol. 25; no. 1; pp. 168 - 182.e6
• Main Authors: Glasgow, Stephen D., Labrecque, Simon, Beamish, Ian V., Aufmkolk, Sarah, Gibon, Julien, Han, Dong, Harris, Stephanie N., Dufresne, Paul, Wiseman, Paul W., McKinney, R. Anne, Séguéla, Philippe, De Koninck, Paul, Ruthazer, Edward S., Kennedy, Timothy E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.10.2018; Elsevier
• Subjects: AMPA receptor trafficking; Animals; axon guidance; CA1 pyramidal neurons; DCC; deleted-in-colorectal cancer; GluR1; Hippocampus - metabolism; long-term potentiation; Long-Term Potentiation - physiology; Mice; Netrin-1 - metabolism; Neurons - metabolism; Receptors, AMPA - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Synapses - metabolism; Synaptic Transmission - physiology; CA1 pyramidal neurons; GluR1; DCC; AMPA receptor trafficking; axon guidance; deleted-in-colorectal cancer; long-term potentiation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.09.028

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. [Display omitted] •Activity-dependent secretion of netrin-1 occurs at dendrites of excitatory neurons•Neuronal netrin-1 is required for long-term potentiation of synaptic transmission•Netrin-1 is sufficient to trigger NMDAR-independent accumulation of GluA1 at synapses•Netrin-1 promotes maturation of immature or nascent synapses Glasgow et al. demonstrate depolarization- and NMDAR-dependent secretion of netrin-1 from the dendrites of hippocampal neurons. They report that genetic deletion of netrin-1 from excitatory neurons impairs hippocampal synaptic plasticity and that netrin-1 application is sufficient to trigger the potentiation of excitatory synaptic transmission via the insertion of GluA1 AMPARs.