Mechanisms and Role of Dendritic Membrane Trafficking for Long-Term Potentiation

Abstract

Long-term potentiation (LTP) of excitatory synapses is a major form of plasticity for learning and memory in the central nervous system. While the molecular mechanisms of LTP have been debated for decades, there is consensus that LTP induction activates membrane trafficking pathways within dendrites that are essential for synapse growth and strengthening. Current models suggest that key molecules for synaptic potentiation are sequestered within intracellular organelles, which are mobilized by synaptic activity to fuse with the plasma membrane following LTP induction. While the identity of the factors mobilized to the plasma membrane during LTP remain obscure, the field has narrowly focused on AMPA-type glutamate receptors. Here, we review recent literature and present new experimental data from our lab investigating whether AMPA receptors trafficked from intracellular organelles directly contribute to synaptic strengthening during LTP. We propose a modified model where membrane trafficking delivers distinct factors that are required to maintain synapse growth and AMPA receptor incorporation following LTP. Finally, we pose several fundamental questions that may guide further inquiry into the role of membrane trafficking for synaptic plasticity.

Surfaceome dynamics reveal proteostasis-independent reorganization of neuronal surface proteins during development and synaptic plasticity

“…A three-step model for AMPA receptor synaptic retention has been proposed that involves exocytosis at extra/perisynaptic sites, lateral diffusion to synapses, and a subsequent rate-limiting diffusional trapping step 59 . While evidence for the importance of surface diffusion is accumulating [60][61][62] , the role of AMPA receptors for the dependence of LTP on exocytosis has not been fully clarified, and there is speculation that currently unrecognized cargo could mediate the requirement for exocytosis [63][64][65][66][67] . While neuron cultures do not undergo LTP, they are frequently stimulated with cLTP treatments which reproduce hallmarks of LTP, such as AMPA receptor exocytosis, synaptic trapping of receptors and increase in synaptic transmission.…”

“…Synaptic recruitment of AMPA receptors from extrasynaptic pools by surface diffusion is required for LTP 60 . Considering the basal extrasynaptic reserve pool of AMPA receptors, the question has been raised whether exocytosis of new AMPA receptors is needed for early LTP or whether other cargo mediates the strict requirement of exocytosis for LTP 63 , 65 – 67 . Signaling mechanisms of synaptic plasticity differ in neuron cultures and hippocampal slices, therefore future studies are required to determine whether our findings from cLTP treatment of cultures are relevant for bona fide LTP.…”

Syntaxin-3 is dispensable for basal neurotransmission and synaptic plasticity in postsynaptic hippocampal CA1 neurons

“…SNARE fusion machinery has been postulated to underlie postsynaptic plasticity by regulating the number and composition of neurotransmitter receptors [10][11][12][13] . In this study, we examined the role of the t-SNARE syntaxin-3 in synaptic transmission and synaptic plasticity in vivo using syntaxin-3 cKO mice ( Figs.…”

“…This suggests that this open Scientific RepoRtS | (2020) 10:709 | https://doi.org/10.1038/s41598-019-57388-6www.nature.com/scientificreports www.nature.com/scientificreports/ v-SNARE is imperative for AMPAR delivery to the postsynaptic membrane during LTP. However, the particular isoforms of t-SNAREs involved in postsynaptic neuronal vesicle fusion remains controversial [10][11][12][13] .A previous study using non-functional recombinant syntaxin-4 revealed that syntaxin-4 mediates activity-dependent AMPAR trafficking to synapses during LTP 14 , whereas another study utilizing syntaxin-3 knockdown (KD) demonstrated that syntaxin-3 is pivotal for the delivery of AMPARs to postsynaptic membranes during LTP, but not syntaxin-4 11 . Therefore, it appears that both syntaxin-3 and syntaxin-4 are potential t-SNAREs that mediate postsynaptic AMPAR delivery during LTP.…”

“…www.nature.com/scientificreports www.nature.com/scientificreports/ v-SNARE is imperative for AMPAR delivery to the postsynaptic membrane during LTP. However, the particular isoforms of t-SNAREs involved in postsynaptic neuronal vesicle fusion remains controversial [10][11][12][13] .…”