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dc.contributor.advisorCosta, Alberto C. S.
dc.contributor.advisorVijayaraghavan, Sukumar
dc.contributor.authorScott-McKean, Jonah Jacob
dc.contributor.committeememberBenke, Timothy A.
dc.contributor.committeememberDell'Acqua, Mark
dc.contributor.committeememberPatterson, David
dc.contributor.committeememberSchoppa, Nathan E.
dc.date.accessioned2007-01-03T04:53:23Z
dc.date.available2014-06-30T08:20:26Z
dc.date.submitted2013
dc.descriptionSpring
dc.descriptionIncludes bibliographical references.
dc.description.abstractDown syndrome (DS) is the most common genetically defined cause of intellectual disabilities and the Ts65Dn mouse is the most researched mouse model for DS. Three major alterations in hippocampal synaptic plasticity have been described in Ts65Dn mice: 1) reduced long-term potentiation (LTP) in the CA1; 2) almost complete absence of LTP in the dentate gyrus; and 3) increased long-term depression (LTD) in the CA1 region. At present, the mechanisms underlying these changes in synaptic plasticity are not well understood. However, there are several human chromosome 21 encoded proteins that are predicted to directly or indirectly impact NMDA receptor function or NMDA-mediated signaling. Given the key role of NMDA receptors in synaptic plasticity and learning and memory, the studies described here may help provide a mechanistic basis for previous electrophysiological and behavioral studies in the Ts65Dn mouse. In this study, we found that the Ts65Dn mouse displays pharmacological responses consistent with a dysfunction in molecular pathways coupled to the gating of NMDA receptors. In particular, the Ts65Dn mouse displayed a hypersensitivity to the locomotor stimulatory effects of the high-affinity NMDA receptor channel blocker, MK-801. In addition, we found that the uncompetitive NMDA receptor antagonist memantine rescue performance deficits of Ts65Dn mice on a fear conditioning test. Based on the well-documented open channel blocking properties of MK-801 and memantine, we propose the hypothesis that NMDA receptors in Ts65Dn mice (and potentially in persons with DS) have an increased mean open time and/or opening probability. We tested this hypothesis further by evaluating the properties of NMDA receptors in Ts65Dn mice using electrophysiological techniques. NMDA-mediated or mGluR-mediated LTD was induced in the CA1 region of hippocampal slices from Ts65Dn and euploid control mice by bath application of NMDA or DHPG, respectively. We found that Ts65Dn mice display exaggerated NMDA-induced, but not mGluR-induced, LTD in the CA1 region of the hippocampus compared with euploid control animals. In addition, this abnormal level of LTD can be pharmacologically rescued by memantine. These results are very promising from a potential therapeutic perspective, given memantine's current status as a FDA-approved drug.
dc.identifierScottMcKean_ucdenveramc_1639D_10016.pdf
dc.identifier.urihttp://hdl.handle.net/10968/261
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.access1-year embargo
dc.rights.accessAccess restricted until June 30, 2014.
dc.subjectTs65Dn
dc.subjectLTD
dc.subject.meshDown Syndrome
dc.subject.meshMemantine
dc.subject.meshLong-Term Synaptic Depression
dc.titlePre-clinical assessment of memantine as a potential therapeutic agent for the treatment of Down Syndrome
dc.typeThesis
dcterms.embargo.expires2014-06-30
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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