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

Author summary Sensation, behavior, and cognition all depend on the proper function of neuronal connections called synapses. Synapses that use the neurotransmitter glutamate to signal between nerve cells are the most abundant type in our brain. Presynaptic neurons release glutamate, which activates glutamate receptors on postsynaptic neurons. Dysfunction of glutamate synapses leads to several neurological disorders, and changing their strength-in part by altering glutamate receptors numbers on the surface of the postsynaptic cell-provides the cellular basis of learning and memory. Much remains to be learned about how factors released from other cell types affects synaptic communication. We took advantage of light-activated molecular switches engineered into specific sensory neurons of C. elegans worms to trigger a behavioral reflex that depends on glutamate synapses. Using this behavior, we identified proteins called VER-1 and VER-4 as important for glutamate synapse function. We found that worms missing these VER proteins or their activator PVF-1 have reduced levels of glutamate receptors at the postsynaptic surface and defects in glutamate-dependent behaviors. Our results suggest that inter-tissue cross-talk between muscle PVF-1 and neuronal VERs is important for controlling the number of glutamate receptors at the cell surface, robust neuronal communication and behavioral responses. 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 as 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 in C. elegans. Loss of function mutations in ver-1, ver-4, or pvf-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 of pvf-1, suggesting that VER function requires endogenous PVF-1. Inducible expression of a pvf-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 model whereby PVF-1/VER signaling acts with retromer to promote recycling and cell surface levels of GLR-1 to control behavior.

Automated summary

Sensation, behavior, and cognition rely on the proper function of neuronal connections known as synapses, with glutamate synapses being the most common in the brain and playing a key role in learning and memory. Research indicates that factors released from other cells can also impact synaptic communication. Through experiments with C. elegans worms, certain proteins were identified as crucial for glutamate synapse function.