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dc.contributor.advisorMurray, Thomas F.en_US
dc.contributor.authorGomez, Dina Akashehen_US
dc.date.accessioned2018-12-18T14:37:30Z
dc.date.available2020-12-15T09:40:13Z
dc.date.issued2018-11-29en_US
dc.identifier.urihttp://hdl.handle.net/10504/120724
dc.description.abstractN-methyl-D-aspartate receptor (NMDAR) dysfunction is associated with many central nervous system disorders such as autism, stroke, and neurodegenerative diseases. Thus, regulation of NMDAR function represents a potential therapeutic strategy. A key pathway that regulates NMDARs is through activation of voltage-gated sodium channels (VGSC)s where elevation of intracellular Na+ renders NMDAR more sensitive to Src family kinase phosphorylation with the attendant increase of Ca2+ influx (Yu and Salter, 1999). Elevation of intracellular calcium activates calcineurin and dephosphorylates the NMDAR limiting further calcium entry (Krupp et al., 2002). Mouse hippocampal neuronal culture (HN) and organotypic hippocampal slice culture (OHSC) were used to study the relationship between neuronal intracellular sodium, calcium and structural plasticity. NMDARs and VGSCs were activated using NMDA and brevetoxin-2 (PbTx-2), respectively. In HN, NMDA and PbTx-2 produced concentration-dependent increases of intracellular calcium. Both NMDA and PbTx-2 induced calcium influx through the NMDARs and L-type calcium channels, however, PbTx-2 also recruited the reverse mode of operation of Na+/Ca2+ exchanger (NCX). The effects of NMDA and PbTx-2 on structural plasticity were dependent on Ca2+ influx through identical pathways. These results demonstrated that NMDA and PbTx-2 induce a bidirectional concentration-response curve in neurite outgrowth, dendritic arborization, and spine density. The data revealed that calcineurin was not responsible for the descending phase of NMDA or PbTx-2 on structural plasticity, though it plays an essential role in NMDAR dephosphorylation. Overall, these studies are consistent with the hypothesis that regulation of NMDAR function through VGSC activation may represent a novel pharmacological strategy to promote neuronal structural plasticity.en_US
dc.language.isoen_USen_US
dc.publisherCreighton Universityen_US
dc.rightsCopyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.en_US
dc.titleVoltage-gated sodium channel and N-methyl-D-aspartate receptor activation affect calcium influx and neuronal structural plasticity in murine hippocampal neuronsen_US
dc.typeDissertation
dc.rights.holderDina Akasheh Gomezen_US
dc.publisher.locationOmaha, Nebraskaen_US
dc.description.noteProQuest Traditional Publishing Optionen_US
dc.contributor.cuauthorGomez, Dina Akashehen_US
dc.embargo.terms2020-12-15
dc.degree.levelPhD (Doctor of Philosophy)en_US
dc.degree.disciplinePharmacology (graduate program)en_US
dc.degree.namePh.D. in Pharmacologyen_US
dc.degree.grantorGraduate Schoolen_US
dc.degree.committeeAbel, Peter W.en_US
dc.degree.committeeScofield, Margareten_US
dc.degree.committeeCerutis, Roselyn D.en_US
dc.degree.committeeDravid, Shashank M.en_US


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