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The characterization of both glial and neuronal mechanisms in the modulation of neuroprotection via the PKG pathway
Title
The characterization of both glial and neuronal mechanisms in the modulation of neuroprotection via the PKG pathway.
Creator
Krill, Jennifer L., Dawson-Scully, Ken, Graduate College
Abstract/Description
Previous work demonstrates that PKG pathway modulation in Drosophila controls tolerance to stress in adults and larvae. Through the use of genetics and pharmacology, PKG inhibition leads to significant protection of function while activation causes increased sensitivity and early coma onset. In this study we investigate the effect of PKG modulation on neurons and glia during acute hyperthermia, and begin to determine the underlying physiological contributions of both tissues. Glia have been...
Show morePrevious work demonstrates that PKG pathway modulation in Drosophila controls tolerance to stress in adults and larvae. Through the use of genetics and pharmacology, PKG inhibition leads to significant protection of function while activation causes increased sensitivity and early coma onset. In this study we investigate the effect of PKG modulation on neurons and glia during acute hyperthermia, and begin to determine the underlying physiological contributions of both tissues. Glia have been found to influence single neuron activity and global brain function. Neurons, the most energy-demanding cells in our bodies, are most sensitive to stress. As humans, our neurons function under stress until permanent failure, resulting in brain damage and even death. Insects are much more tolerant to environmental stressors. Although stress-activated protective pathways are highly conserved in both insects and humans, their outcome on neuronal function and survival are very different.
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Date Issued
2014
PURL
http://purl.flvc.org/fau/fd/FA00005829
Format
Document (PDF)
cGMP-Dependent Protein Kinase Inhibition Extends the Upper Temperature Limit of Stimulus-Evoked Calcium Responses in Motoneuronal Boutons of Drosophila melanogaster Larvae
Title
cGMP-Dependent Protein Kinase Inhibition Extends the Upper Temperature Limit of Stimulus-Evoked Calcium Responses in Motoneuronal Boutons of Drosophila melanogaster Larvae.
Creator
Krill, Jennifer L., Dawson-Scully, Ken, McCabe, Brian D.
Abstract/Description
While the mammalian brain functions within a very narrow range of oxygen concentrations and temperatures, the fruit fly, Drosophila melanogaster, has employed strategies to deal with a much wider range of acute environmental stressors. The foraging (for) gene encodes the cGMP-dependent protein kinase (PKG), has been shown to regulate thermotolerance in many stress-adapted species, including Drosophila, and could be a potential therapeutic target in the treatment of hyperthermia in mammals....
Show moreWhile the mammalian brain functions within a very narrow range of oxygen concentrations and temperatures, the fruit fly, Drosophila melanogaster, has employed strategies to deal with a much wider range of acute environmental stressors. The foraging (for) gene encodes the cGMP-dependent protein kinase (PKG), has been shown to regulate thermotolerance in many stress-adapted species, including Drosophila, and could be a potential therapeutic target in the treatment of hyperthermia in mammals. Whereas previous thermotolerance studies have looked at the effects of PKG variation on Drosophila behavior or excitatory postsynaptic potentials at the neuromuscular junction (NMJ), little is known about PKG effects on presynaptic mechanisms. In this study, we characterize presynaptic calcium ([Ca^2+]i) dynamics at the Drosophila larval NMJ to determine the effects of high temperature stress on synaptic transmission. We investigated the neuroprotective role of PKG modulation both genetically using RNA interference (RNAi), and pharmacologically, to determine if and how PKG affects presynaptic [Ca^2+]i dynamics during hyperthermia. We found that PKG activity modulates presynaptic neuronal Ca^2+ responses during acute hyperthermia, where PKG activation makes neurons more sensitive to temperatureinduced failure of Ca^2+ flux and PKG inhibition confers thermotolerance and maintains normal Ca^2+ dynamics under the same conditions. Targeted motoneuronal knockdown of PKG using RNAi demonstrated that decreased PKG expression was sufficient to confer thermoprotection. These results demonstrate that the PKG pathway regulates presynaptic motoneuronal Ca^2+ signaling to influence thermotolerance of presynaptic function during acute hyperthermia.
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Date Issued
2016-10-06
PURL
http://purl.flvc.org/fau/fd/FAUIR000079
Format
Citation
Glial Hsp70 Protects K+ Homeostasis in the Drosophila Brain during Repetitive Anoxic Depolarization
Title
Glial Hsp70 Protects K+ Homeostasis in the Drosophila Brain during Repetitive Anoxic Depolarization.
Creator
Armstrong, Gary A. B., Xiao, Chengfeng, Krill, Jennifer L., Seroude, Laurent, Dawson-Scully, Ken, Robertson, R. Meldrum, Roman, Gregg
Abstract/Description
Neural tissue is particularly vulnerable to metabolic stress and loss of ion homeostasis. Repetitive stress generally leads to more permanent dysfunction but the mechanisms underlying this progression are poorly understood. We investigated the effects of energetic compromise in Drosophila by targeting the Na+/K+-ATPase. Acute ouabain treatment of intact flies resulted in subsequent repetitive comas that led to death and were associated with transient loss of K+ homeostasis in the brain. Heat...
Show moreNeural tissue is particularly vulnerable to metabolic stress and loss of ion homeostasis. Repetitive stress generally leads to more permanent dysfunction but the mechanisms underlying this progression are poorly understood. We investigated the effects of energetic compromise in Drosophila by targeting the Na+/K+-ATPase. Acute ouabain treatment of intact flies resulted in subsequent repetitive comas that led to death and were associated with transient loss of K+ homeostasis in the brain. Heat shock pre-conditioned flies were resistant to ouabain treatment. To control the timing of repeated loss of ion homeostasis we subjected flies to repetitive anoxia while recording extracellular [K+] in the brain. We show that targeted expression of the chaperone protein Hsp70 in glial cells delays a permanent loss of ion homeostasis associated with repetitive anoxic stress and suggest that this is a useful model for investigating molecular mechanisms of neuroprotection.
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Date Issued
2011-12-12
PURL
http://purl.flvc.org/fau/fd/FAUIR000078
Format
Citation
Neuroprotection during acute hyperthermic stress: Role of the PKG pathway in neurons and glia in the protection of neural function in Drosophila melanogaster
Title
Neuroprotection during acute hyperthermic stress: Role of the PKG pathway in neurons and glia in the protection of neural function in Drosophila melanogaster.
Creator
Krill, Jennifer L., Dawson-Scully, Ken, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description
The human brain functions within a narrow range of temperatures and variations outside of this range incur cellular damage and death and, ultimately, death of the organism. Other organisms, like the poikilotherm Drosophila melanogaster, have adapted mechanisms to maintain brain function over wide ranges in temperature and, if exposed to high temperatures where brain function is no longer supported, these animals enter a protective coma to promote survival of the organism once the acute...
Show moreThe human brain functions within a narrow range of temperatures and variations outside of this range incur cellular damage and death and, ultimately, death of the organism. Other organisms, like the poikilotherm Drosophila melanogaster, have adapted mechanisms to maintain brain function over wide ranges in temperature and, if exposed to high temperatures where brain function is no longer supported, these animals enter a protective coma to promote survival of the organism once the acute temperature stress is alleviated. This research characterized the role of different neuronal cell types, including glia, in the protection of brain function during acute hyperthermia, specifically looking at two protective pathways: the heat shock protein (HSP) pathway and the cGMP-dependent protein kinase G (PKG) pathway. Whole animal behavioral assays were used in combination with tissue-specific genetic manipulation of protective pathways to determine the specific cell types sufficient to confer protection of neuronal function during acute hyperthermia. Using the neuromuscular junction (NMJ) preparation, calcium imaging techniques were combined with pharmacological and genetic manipulations to test the hypothesis that alterations in ion channel conductance via endogenous mechanisms regulating the cellular response to high temperature stress alter neuronal function. Expression of foraging RNAi to inhibit PKG expression in neurons or glia demonstrated protection of function during acute hyperthermia measured behaviorally through the extension of locomotor function. This extension of function with the tissue-specific inhibition of PKG was also confirmed at the cellular level using the genetically encoded calcium indicator (GECI), GCaMP3, to image calcium dynamics at the NMJ, where preparations expressing foraging RNAi could continue to elicit changes in calcium dynamics in response to stimulation. Over the course of this study, the mechanism underlying a novel glial calcium wave in the peripheral nervous system was characterized in order to elucidate glia’s role in the protection of neuronal function during acute hyperthermia.
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Date Issued
2018
PURL
http://purl.flvc.org/fau/fd/FA00013026
Subject Headings
Cyclic GMP-Dependent Protein Kinases, Neuroprotection, Hyperthermia, Heat shock proteins, Drosophila melanogaster
Format
Document (PDF)