Reactive Oxygen Species Modulate Activity-Dependent AMPA Receptor Transport in C. elegans

Abstract

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.

An Electrophysiological and Proteomic Analysis of the Effects of the Superoxide Dismutase Mimetic, MnTMPyP, on Synaptic Signalling Post-Ischemia in Isolated Rat Hippocampal Slices

“…In addition, the application of DPCPX, DCKA and AP5 have been previously reported to reverse the protective effects of MnTMPyP on synaptic transmission post-ischemia [ 20 ]. It has been reported that superoxide is produced by NMDA receptors in an attempt to achieve a state of NMDA receptor hypofunction in order to limit damaging Ca 2+ influx [ 58 ].…”

Modulation of sensory perception by hydrogen peroxide enables Caenorhabditis elegans to find a niche that provides both food and protection from hydrogen peroxide

“…Previous studies in C . elegans showed that H 2 O 2 blocks inactivating currents in ASER [ 81 ] and that pretreatment with H 2 O 2 blocked subsequent excitation of ASH sensory neurons by specific inputs [ 82 , 83 ] and lowered the spontaneous activity of AVA interneurons [ 84 ]. The H 2 O 2 concentration that we used in our studies is within the range produced by bacterial pathogens [ 19 – 21 ] and detected in inflammation or reperfusion after ischemia in mammals [ 85 , 86 ].…”

Modulation of sensory perception by hydrogen peroxide enables Caenorhabditis elegans to find a niche that provides both food and protection from hydrogen peroxide

“…We note that H 2 O 2 prevented the responses to E. coli of a wide variety of sensory neurons. Previous studies in C. elegans showed that H 2 O 2 blocks inactivating currents in ASER (Cai and Sesti, 2009) and that pretreatment with H 2 O 2 blocked subsequent excitation of ASH sensory neurons by specific inputs (Li et al, 2016; Zhang et al, 2020) and lowered the spontaneous activity of AVA interneurons (Doser et al, 2020). The H 2 O 2 concentration that we used in our studies is within the range produced by bacterial pathogens (Bolm et al, 2004; Jansen et al, 2002; Moy et al, 2004) and detected in inflammation or reperfusion after ischemia in mammals (Schroder and Eaton, 2008; Sprong et al, 1997).…”