Activity-dependent netrin-1 secretion drives synaptic insertion of GluA1-containing AMPA receptors in the hippocampus

Abstract

Dynamic trafficking of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs) to synapses is critical for activity-dependent synaptic plasticity underlying learning and memory, however 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 NMDARdependent long-term potentiation (LTP) in the adult hippocampus. Further, we demonstrate that application of exogenous netrin-1 is sufficient to trigger the potentiation of excitatory glutamatergic transmission at hippocampal Schaffer collateral synapses via Ca 2+ -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.

Spatial memory formation requires netrin-1 expression by neurons in the adult mammalian brain.

“…Further, application of exogenous netrin-1 is sufficient to trigger insertion of GluA1-containing a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs). Together, these findings indicate that netrin-1 participates in activity-dependent plasticity at Schaffer-collateral synapses, that netrin-1 is secreted by neurons in response to activity, and that netrin-1 is sufficient to evoke lasting synaptic potentiation (Glasgow et al 2018). Here we report that conditional deletion of netrin-1 from principal excitatory neurons results in deficits in hippocampal-dependent spatial memory, demonstrating that netrin-1 critically regulates memory processes underlying spatial cognition.…”

“…We have recently reported that neuronal expression of netrin-1 in principal excitatory neurons impairs long-term potentiation in the adult hippocampus, suggesting that netrin-1 may be necessary for spatial memory formation (Glasgow et al 2018). To test the hypothesis that netrin-1 made by glutamatergic neurons in the forebrain contributes to memory formation, we tested CaMKII-Cre/NTN1 f/f (NTN1 cKO) and wild-type age-matched littermate controls in the hippocampus-dependent Morris water maze (MWM) task (Morris et al 1982).…”

“…Netrin-1 and DCC are highly enriched at synapses in the mature mammalian brain and DCC co-fractionates with detergent-resistant components of the post-synaptic density (Horn et al 2013). We have recently reported that netrin-1 is released at synaptic sites in response to N-methyl-D-aspartate glutamate receptor (NMDAR) activation and is critical for expression of long-term potentiation at hippocampal Schaffer-collateral synapses, an experimental model of synaptic plasticity in the adult brain (Glasgow et al 2018). Further, application of exogenous netrin-1 is sufficient to trigger insertion of GluA1-containing a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs).…”

Deleted in colorectal cancer (netrin‐1 receptor) antibodies and limbic encephalitis in a cat with hippocampal necrosis

“…17 DCC regulates synaptic function including NMDA receptordependent synaptic plasticity in maturated brains. 18,19 Anti-DCC autoantibodies are associated more with thymoma and myasthenia gravis and less with LE. 8,20 In 1 human study, however, 4 of 12 patients with DCC antibodies were diagnosed as LE although F I G U R E 4 The case cat serum antibodies do not bind to leucinerich glioma inactivated 1 (LGI1).…”

“…Recent studies suggested DCC and netrin-1 contribution to synaptic excitation. 18,19 Therefore, the possibility of direct contribution of DCC antibodies to the pathogenesis of LE should be considered in the future.…”