The Role of the Neuronal gap Junction Protein Connexin36 in Kainic Acid Induced Hippocampal Excitotoxicity

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dc.contributor.authorAkins, Mark S.
dc.date.accessioned2014-01-08T21:57:49Z
dc.date.available2015-01-09T09:00:07Z
dc.date.created2014
dc.date.issued2014
dc.identifier.urihttp://hdl.handle.net/10393/30392
dc.identifier.urihttp://dx.doi.org/10.20381/ruor-6778
dc.description.abstractKainic acid induced excitotoxicity causes pyramidal cell death in the CA3a/b region of the hippocampus. Electrical synapses, gap junctional communication, and single membrane channels in non-junctional membranes (hemichannels) composed of connexin36 (Cx36) have been implicated in both seizure propagation and the spread of excitotoxic cell death. In rats, Cx36 protein is expressed by pyramidal neurons. Localization of protein in mouse, however, is highly controversial. Expression is reported to be restricted to hippocampal interneurons yet the same excitotoxic mechanisms (electrical and metabolic coupling between pyramidal neurons) are invoked to explain the role of Cx36 in excitotoxic pyramidal loss in murine brain. To address this controversy, I show by confocal immunofluorescence and in situ hybridization that Cx36 protein expression is restricted to interneurons and microglia in murine hippocampus and is not expressed by, or is below level of detection in pyramidal neurons. Using behavioural and electrophysiological measures, seizure propagation was found to be moderately enhanced in the absence of Cx36 likely due to the loss of interneuron-mediated synchronous inhibition of the pyramidal cells. Further, CA3a/b neurons die post kainic acid injury in the presence of Cx36 but are protected in Cx36-/- mice. When delayed excitotoxic cell death is maximal, Cx36 is primarily expressed by activated microglia as demonstrated by confocal immunofluorescence, in situ hybridization, and Western blotting. These activated microglia are located in the direct vicinity of, and surrounding cells in the damaged Ca3a/b region. Finally, I show that loss of Cx36 from activated microglia in mice is sufficient to prevent excitotoxic cell death in the CA3a/b with surviving neurons functional as assessed by both electrophysiological and behavioural measures. Together, these data identify a new mechanism of excitotoxic injury, mediated by neuronal-glial interactions, and dependent on microglial Cx36 expression.
dc.language.isoen
dc.publisherUniversité d'Ottawa / University of Ottawa
dc.subjectKainic acid
dc.subjectExcitotoxic injury
dc.subjectExcitotoxicity
dc.subjectNeuron
dc.subjectNeuronal survival
dc.subjectConnexin36
dc.subjectConnexin
dc.subjectPyramidal cell
dc.subjectInterneuron
dc.subjectHippocampus
dc.subjectMicroglia
dc.subjectNeural protection
dc.subjectSeizure
dc.titleThe Role of the Neuronal gap Junction Protein Connexin36 in Kainic Acid Induced Hippocampal Excitotoxicity
dc.typeThesis
dc.faculty.departmentBiochimie, microbiologie et immunologie / Biochemistry, Microbiology and Immunology
dc.contributor.supervisorBennett, Steffany
dc.embargo.terms1 year
dc.degree.nameMSc
dc.degree.levelmasters
dc.degree.disciplineMédecine / Medicine
thesis.degree.nameMSc
thesis.degree.levelMasters
thesis.degree.disciplineMédecine / Medicine
uottawa.departmentBiochimie, microbiologie et immunologie / Biochemistry, Microbiology and Immunology
CollectionThèses, 2011 - // Theses, 2011 -

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