VER/VEGF receptors regulate AMPA receptor surface levels and glutamatergic behavior

by Eric S. Luth, Molly Hodul, Bethany J. Rennich, Carmino Riccio, Julia Hofer, Kaitlin Markoja, Peter Juo

Several intracellular trafficking pathways contribute to the regulation of AMPA receptor (AMPAR) levels at synapses and the control of synaptic strength. While much has been learned about these intracellular trafficking pathways, a major challenge is to understand how extracellular factors, such a s growth factors, neuropeptides and hormones, impinge on specific AMPAR trafficking pathways to alter synaptic function and behavior. Here, we identify the secreted ligand PVF-1 and its cognate VEGF receptor homologs, VER-1 and VER-4, as regulators of glutamate signaling inC.elegans. Loss of function mutations inver-1,ver-4, orpvf-1, result in decreased cell surface levels of the AMPAR GLR-1 and defects in glutamatergic behavior. Rescue experiments indicate that PVF-1 is expressed and released from muscle, whereas the VERs function in GLR-1-expressing neurons to regulate surface levels of GLR-1 and glutamatergic behavior. Additionally,ver-4 is unable to rescue glutamatergic behavior in the absence ofpvf-1, suggesting that VER function requires endogenous PVF-1. Inducible expression of apvf-1 rescuing transgene suggests that PVF-1 can function in the mature nervous system to regulate GLR-1 signaling. Genetic double mutant analysis suggests that the VERs act together with the VPS-35/retromer recycling complex to promote cell surface levels of GLR-1. Our data support a genetic mod...

Source: PLoS Genetics - February 9, 2021 Category: Genetics & Stem Cells Authors: Eric S. Luth Source Type: research