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.
Highlights
Glutamatergic synaptic transmission in the adult brain is primarily mediated by a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs), with changes in synaptic strength due to alterations in both synaptic structure and receptor composition (Bosch and Hayashi, 2012; Kessels and Malinow, 2009)
To determine if increased neuronal spiking induces secretion of netrin-1, we used the designer receptors exclusively activated by designer drugs (DREADD) approach to excite primary hippocampal neurons infected with AAV8-Syn-hM3D(Gq)-mCitrine
We observed significant increases in AMPAR-mediated current and AMPAR-to-N-methyl-D-aspartate receptor (NMDAR) ratio in slices from control littermates following tetanic stimulation, but not in slices from NTN1 cKO mice (Figures 2F–2H). These findings demonstrate that deletion of ntn1 from principal excitatory neurons significantly attenuates NMDAR-dependent Long-term potentiation (LTP) and indicate that netrin-1 plays a central role in synaptic plasticity in the adult hippocampus
Summary
Glutamatergic synaptic transmission in the adult brain is primarily mediated by a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs), with changes in synaptic strength due to alterations in both synaptic structure and receptor composition (Bosch and Hayashi, 2012; Kessels and Malinow, 2009). Long-term potentiation (LTP), an intensively studied experimental model of synaptic plasticity and memory, modifies postsynaptic function through N-methyl-D-aspartate receptor (NMDAR)-dependent recruitment of AMPARs, cytoskeletal reorganization, and modification of synaptic adhesion (Bosch et al, 2014; Kasai et al, 2010). The netrin receptor deleted in colorectal cancer (DCC) directs cell motility by regulating intracellular calcium, RhoGTPases, Src family kinases, focal adhesion kinase, phospholipase C, phosphoinositol 3-kinase, p21-activated kinase, and local protein synthesis, all of which influence adhesion, cytoskeletal organization, and synapse function (Lai Wing Sun et al, 2011). A form of synaptic consolidation in Aplysia neurons, studied in primary cell culture, requires netrin-1-dependent local protein synthesis, suggesting a critical role for netrin-1 in the modification of synaptic function (Kim and Martin, 2015). Several families of ligands have been identified for DCC, including draxins, cerebellins, and netrins (Ahmed et al, 2011; Wei et al, 2012); the enrichment of netrin-1 at synapses suggests that it may be a key ligand for DCC to regulate synaptic function
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