The AMPA subtype of synaptic glutamate receptors (AMPARs) play an essential role in cognition. Their function, numbers and change at synapses during synaptic plasticity, is tightly regulated by neuronal activity. Although we know that long-distance transport of AMPARs is essential for this regulation, we don’t understand the regulatory mechanisms of it. Neuronal transmission is a metabolically demanding process in which ATP consumption and production are tightly coupled and regulated. Aerobic ATP synthesis unavoidably produces reactive oxygen species (ROS), such as hydrogen peroxide, which are known modulators of calcium signaling. Although a role for calcium signaling in AMPAR transport has been described, there is little understanding of the mechanisms involved and no known link to physiological ROS signaling. Here, using real-time in vivo imaging of AMPAR transport in the intact C. elegans nervous system, we demonstrate that long-distance synaptic AMPAR transport is bidirectionally regulated by calcium influx and activation of calcium/calmodulin-dependent protein kinase II. Quantifying in vivo calcium dynamics revealed that modest, physiological increases in ROS decrease calcium transients in C. elegans glutamatergic neurons. By combining genetic and pharmacological manipulation of ROS levels and calcium influx, we reveal a mechanism in which physiological increases in ROS cause a decrease in synaptic AMPAR transport and delivery by modulating activity-dependent calcium signaling. Taken together, our results identify a novel role for oxidant signaling in the regulation of synaptic AMPAR transport and delivery, which in turn could be critical for coupling the metabolic demands of neuronal activity with excitatory neurotransmission.SIGNIFICANCE AND IMPACTSynaptic AMPARs are critical for excitatory synaptic transmission. The disruption of their synaptic localization and numbers is associated with numerous psychiatric, neurological, and neurodegenerative conditions. However, very little is known about the regulatory mechanisms controlling transport and delivery of AMPAR to synapses. Here, we describe a novel physiological signaling mechanism in which ROS, such as hydrogen peroxide, modulate AMPAR transport by modifying activity-dependent calcium influx. Our findings provide the first evidence in support of a mechanistic link between physiological ROS signaling, AMPAR transport, localization, and excitatory transmission. Of potential therapeutic importance, dysregulation of intracellular calcium and ROS signaling is implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer’s and Parkinson’s disease.

The AMPA subtype of synaptic glutamate receptors (AMPARs) plays an essential role in cognition. Their function, numbers, and change at synapses during synaptic plasticity are tightly regulated by neuronal activity. Although we know that long-distance transport of AMPARs is essential for this regulation, we do not understand the associated regulatory mechanisms of it. Neuronal transmission is a metabolically demanding process in which ATP consumption and production are tightly coupled and regulated. Aerobic ATP synthesis unavoidably produces reactive oxygen species (ROS), such as hydrogen peroxide, which are known modulators of calcium signaling. Although a role for calcium signaling in AMPAR transport has been described, there is little understanding of the mechanisms involved and no known link to physiological ROS signaling. Here, using realtime in vivo imaging of AMPAR transport in the intact C. elegans nervous system, we demonstrate that long-distance synaptic AMPAR transport is bidirectionally regulated by calcium influx and activation of calcium/calmodulin-dependent protein kinase II. Quantification of in vivo calcium dynamics revealed that modest, physiological increases in ROS decrease calcium transients in C. elegans glutamatergic neurons. By combining genetic and pharmacological manipulation of ROS levels and calcium influx, we reveal a mechanism in which physiological increases in ROS cause a decrease in synaptic AMPAR transport and delivery by modulating activity-dependent calcium signaling. Together, our results identify a novel role for oxidant signaling in the regulation of synaptic AMPAR transport and delivery, which in turn could be critical for coupling the metabolic demands of neuronal activity with excitatory neurotransmission.

Caenorhabditis elegans is an important genetic model for neuroscience studies, used for analyses of how genes control connectivity, neuronal function, and behavior. To date, however, most studies of neuronal function...

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