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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Hippocampus / metabolism*
  • Long-Term Potentiation / physiology
  • Mice
  • Netrin-1 / metabolism*
  • Neurons / metabolism
  • Receptors, AMPA / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / metabolism*
  • Synaptic Transmission / physiology*

Substances

  • Ntn1 protein, mouse
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Netrin-1
  • glutamate receptor ionotropic, AMPA 1

Grant support