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dc.contributor.authorRiggs, Lace Marie
dc.date.accessioned2022-06-14T18:38:22Z
dc.date.available2022-06-14T18:38:22Z
dc.date.issued2022
dc.identifier.urihttp://hdl.handle.net/10713/19169
dc.descriptionUniversity of Maryland, Baltimore. Neuroscience. Ph.D. 2022.en_US
dc.description.abstractKetamine rapidly alleviates symptoms of treatment-resistant major depression within hours of a single administration. While this may offer a new and promising trajectory for novel therapeutic development, rapid antidepressant mechanisms of action have proven especially enigmatic. Here, I applied an in vitro-à-in vivo approach to identify the cellular actions of (2R,6R)-hydroxynorketamine (HNK) – a secondary metabolite of ketamine that exerts rapid antidepressant-like effects sine dissociative properties and abuse potential. I found that (2R,6R)-HNK promotes a rapid potentiation of glutamate release at hippocampal Schaffer collateral synapses, an important site of antidepressant action that serves as a conduit in the regulation of mood and cognition. This potentiation proved to be a synapse-selective calcium-mediated phenomenon that involves the rapid induction of cyclic adenosine monophosphate dependent protein kinase, known to actuate vesicle-associated phosphoproteins to enhance glutamate release. These properties confer (2R,6R)-HNK with an ability to restore Schaffer collateral-dependent plasticity and cognitive function in a preclinical model of treatment-resistant major depression. My findings are the first to establish a cellular mechanism by which (2R,6R)-HNK gives rise to sustained adaptations in synaptic transmission and behavior and provides a novel framework for the development of improved therapeutic options for depression.en_US
dc.language.isoen_USen_US
dc.subjecthydroxynorketamineen_US
dc.subject.meshDepressionen_US
dc.subject.meshElectrophysiologyen_US
dc.subject.meshHippocampusen_US
dc.subject.meshMemoryen_US
dc.subject.meshAntidepressive Agentsen_US
dc.titleSynaptic Mechanisms Underlying the Rapid Antidepressant Properties of the (2R,6R)-Hydroxynorketamine Ketamine Metaboliteen_US
dc.typedissertationen_US
dc.date.updated2022-06-10T22:13:00Z
dc.language.rfc3066en
dc.contributor.advisorGould, Todd D.
dc.contributor.orcid0000-0003-4368-4089


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