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dc.contributor.advisorBrooks-Kayal, Amy
dc.contributor.authorThomas, Ajay
dc.contributor.committeememberRibera, Angeles
dc.contributor.committeememberBenke, Timothy
dc.contributor.committeememberJones, Kevin
dc.contributor.committeememberMacklin, Wendy
dc.contributor.committeememberPatel, Manisha
dc.date.accessioned2015-08-27T03:56:09Z
dc.date.available2017-08-19T08:20:26Z
dc.date.submitted2015
dc.descriptionSummer
dc.descriptionIncludes bibliographical references.
dc.description.abstractBrain-Derived Neurotrophic Factor (BDNF) expression is elevated after status epilepticus (SE), leading to rapid activation of multiple signaling pathways, including the Signal Transducer and Activator of Transcription 3 (STAT3) pathway that mediates a decrease in GABAᴀ receptor α1 subunit expression in hippocampus (Lund et al., 2008). While BDNF can signal via its pro- or mature form, the relative contribution of these forms to signaling after SE is not fully known. In the current study, induce SE in C57BL/6J mice. A thorough review of temporal lobe epilepsy models is reported with special emphasis on models useful in C57BL/6J mice. Animals in the current study underwent repetitive low dose pilocarpine (RLDP) to induce SE. Development of intrahippocampal kainic acid induced SE was also initiated to decrease mortality and increase effectiveness of SE when compared to RLDP. I also investigate the relative change in the expression of proBDNF and mBDNF after SE using BDNF-epitope tagged knock-in mice. In contrast to previous reports (Unsain et al., 2008; Volosin et al., 2008; VonDran et al., 2014), our studies found that levels of proBDNF in hippocampus are markedly elevated as early as three hours after SE onset and remain elevated for 24 hours, with no increase in mBDNF levels detected. Immunohistochemistry studies indicate that seizure-induced BDNF increases occur in all hippocampal subfields, predominantly in principal neurons but also in astrocytes. Analysis of the proteolytic machinery that acts on proBDNF to produce mBDNF demonstrated that acutely after SE, there is a decrease in tissue plasminogen activator (tPA), part of the extracellular proteolytic cascade, and an increase in plasminogen activator inhibitor-1 (PAI-1), an inhibitor of extracellular and intracellular cleavage. These findings suggest that proBDNF increases rapidly following SE, likely due to both increased synthesis and reduced cleavage into mBDNF, and that proBDNF may be the initial neurotrophin signal driving intracellular signaling during the acute phase of epileptogenesis.
dc.identifierThomas_ucdenveramc_1639D_10237.pdf
dc.identifier.urihttp://hdl.handle.net/10968/1138
dc.languageEnglish
dc.publisherUniversity of Colorado Anschutz Medical Campus. Strauss Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.rights.accessEmbargo Expires: 08/19/2017
dc.subjectCleavage
dc.subject.meshBrain-Derived Neurotrophic Factor
dc.subject.meshEpilepsy
dc.subject.meshMice
dc.subject.meshNerve Growth Factors
dc.subject.meshPilocarpine
dc.titleRapid increases in ProBDNF after pilocarpine-induced status epilepticus in mice are associated with reduced ProBDNF cleavage machinery
dc.typeThesis
dcterms.embargo.expires2017-08-19
thesis.degree.disciplineNeuroscience
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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