The Retromer Supports AMPA Receptor Trafficking During LTP

SNX27 is required for LTP, and alterations in this pathway prevent cLTP by impairing the activity-dependent recruitment of surface AMPA receptors.

“Similar to SNX17, SNX27 is also required for LTP. Alterations in this pathway prevent cLTP by impairing the activity-dependent recruitment of surface AMPA receptors”

LTP-dependent recycling of AMPARs from intracellular compartments is dependent on the SNX27 pathway.

“Among the best characterized is the LTP-dependent recycling of AMPARs from intracellular compartments, which is dependent on the SNX27 pathway (Temkin et al., 2017; Loo et al., 2014; Hussain et al., 2014; Wang et al., 2013).”

Knockdown of SNX27 blocks cLTP induction in cultured rat hippocampal neurons.

“Similarly, knockdown of SNX27 also blocked cLTP (Figure 5E–G), again similar to earlier reports (Loo et al., 2014; Hussain et al., 2014; see also, Temkin et al., 2017).”

The SNX27-Retromer pathway is required for proper AMPAR recycling.

“the SNX27-Retromer pathway is known to be required for proper AMPAR recycling (Choy et al., 2014; Hussain et al., 2014; Temkin et al., 2017).”

VPS35 suppression decreased surface levels of GLUT1/SLC2A1, AMPA receptors GRIA2, GRIA3, GRIA4, NMDA receptors GRIN1, GRIN2b, and SLC4A7.

“Validating our approach, downregulated proteins included the wellestablished Retromer cargo glucose transporter-1 (GLUT1/SLC2A1) [29], the ionotropic glutamate AMPA receptors (GRIA2, GRIA3, GRIA4) and NMDA receptors (GRIN1, GRIN2b) [80][81][82][83][84][85], as well as many other previously identified proteins including the sodium bicarbonate cotransporter-3 (SLC4A7) (Figure 1D, Supplementary Table”

Loss of GluA1 and the ensuing synaptic pathology occurs in the setting of retromer dysfunction independent of both amyloid and tau pathology.

“Since previous studies have shown that VPS35 depletion results in GluA1 loss in the absence of APP (Temkin et al., 2017), we can conclude that loss of GluA1, and the synaptic pathology that ensues, occurs in the setting of retromer dysfunction independent of both AD-associated amyloid or tau pathology.”

Retromer dysfunction is associated with pathogenic cleavage of amyloid precursor protein and loss of hippocampal-enriched glutamate receptors.

“For neurons, we relied on prior studies that have associated retromer dysfunction with the pathogenic cleavage of the amyloid precursor protein (APP) and the loss of hippocampal-enriched glutamate receptors (Temkin et al., 2017), which typify AD-associated amyloid and synaptic pathology.”

The phenotype of glutamate receptor loss is regulated by retromer in the intact hippocampus.

“we extend previous work in the hippocampal slice (Temkin et al., 2017) to show that this phenotype is regulated by retromer in the intact hippocampus.”

Loss of VPS35 impairs Gria1 (AMPA) receptor insertion and disrupts LTP, while restoring VPS35 reverses these deficits.

“Loss of VPS35 impairs Gria1 (AMPA) receptor insertion and disrupts LTP, while restoring VPS35 reverses these deficits [39].”

The retromer complex regulates pre-synaptic vesicle release.

“recent studies which have demonstrated the role of the retromer complex system in the regulation of pre-synaptic vesicle release [22, 23]”

The retromer complex regulates post-synaptic trafficking of AMPA receptors.

“and post-synaptic trafficking of AMPA receptors [23].”