Reactive oxygen species regulate activity-dependent transport and delivery of AMPA receptors to synapses
Date
2022
Authors
Doser, Rachel, author
Hoerndli, Frederic, advisor
Amberg, Gregory, advisor
Di Pietro, Santiago, committee member
Vigh, Jozsef, committee member
Journal Title
Journal ISSN
Volume Title
Abstract
In neurons, changes in the subcellular localization of the AMPA subtype of ionotropic glutamate receptors (AMPARs) is necessary for learning and memory. AMPARs are primarily translated in the cell body and transported through dendrites to their destinations by molecular motors. This means that their localization, and therefore synaptic function and plasticity, requires proper intracellular transport to the synapse. Our lab and others have shown that AMPAR transport is regulated by activity-dependent calcium signaling. Neuronal activity and intracellular transport are energy demanding requiring high rates of ATP production from which reactive oxygen species (ROS), a class of chemically reactive molecules, are a normal byproduct. For my dissertation work, I build upon this knowledge by demonstrating a physiological role for ROS in the regulation of AMPAR transport in the transparent genetic model C. elegans. In Chapter 2, we show that slight increases in ROS decreased transport and synaptic delivery of AMPARs by attenuating calcium influx. Diminished ROS levels also decreased AMPAR transport but via a calcium-independent mechanism. This prompted us to assess how ROS signaling is initiated in vivo, which was the aim of experiments in Chapter 3. The results from these experiments demonstrated that calcium buffering and ROS production at mitochondria are positively regulated by activity. So, the rest of Chapter 3 was devoted to experiments addressing how AMPAR transport dynamics are impacted by localized ROS signaling originating at mitochondria. In the neurite, we found that localized increases in ROS from mitochondria regulate the stopping of AMPAR transport events by potentially altering local calcium influx. Further investigation on how local calcium influx, mitochondrial ROS production and AMPAR transport are interrelated in vivo necessitates optimization of optogenetic tools for high spatial and temporal control of cytoplasmic calcium levels. To this end, Chapter 4 overviews the optimization and characterization of a few optogenetic approaches for simultaneously manipulating and measuring neuronal activity in vivo. This work begins to detail how ROS signaling regulates synaptic function and plasticity which describes a novel mechanism in which metabolic rate indirectly regulates synaptic activity. Understanding this mechanism would provide insight into why altered glutamatergic synaptic transmission accompanies elevated calcium/ROS and mitochondrial dysfunction in neuronal aging and degeneration.
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Embargo Expires: 06/05/2024
Subject
glutamate receptors
mitochondria
synapses
intracellular transport
calcium signaling
reactive oxygen species