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dc.contributor.authorVan Dyke, Adam M.
dc.date.accessioned2016-06-28T17:02:17Z
dc.date.available2016-06-28T17:02:17Z
dc.date.issued2016
dc.identifier.urihttp://hdl.handle.net/10713/5469
dc.descriptionUniversity of Maryland, Baltimore. Neuroscience. Ph.D. 2016en_US
dc.description.abstractSerotonin and its receptors have long been major targets in the pharmacological treatment of depression. Despite their widespread use, the mechanism of action underlying the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs) like fluoxetine remains poorly understood. I used combination of electrophysiology, molecular biology, and behavioral assays in rats and mice to investigate the actions of serotonin signaling on neuronal function in an attempt to understand the fundamental question, "How do antidepressants work?" I chose to focus on the actions of serotonin in the hippocampus, an area of the brain that exhibits robust changes in depression. The temporoammonic to CA1 pyramidal cell glutamatergic synapses exhibit a pathological weakening in depression models and are restored following successful antidepressant treatment. Our laboratory has shown that serotonin can potentiate these synapses via activation of 5-HT1B receptors (5-HT1BRs) and subsequent phosphorylation of the AMPA receptor subunit GluA1 at S831; this potentiation is necessary for the therapeutic action of antidepressants. I first identified which signaling pathways were recruited following 5-HT1BR activation and describe the impact of these molecules on glutamatergic transmission. My results describe the convergence of multiple second messenger pathways underlying the synaptic potentiation. 5-HT1BR activation recruits a PLC/Ca2+/CaMKII second messenger cascade that phosphorylates GluA1 at S831 and underlies the change in synaptic strength. I also describe a permissive Ras/Raf/MEK/ERK signaling cascade that allows activate CaMKII to phosphorylate its GluA1 substrate. With a greater understanding of the molecules recruited by serotonin, I describe how elevation of endogenous serotonin by the SSRI fluoxetine results in the simultaneous co-activation of multiple serotonin receptors. I conclude that activation of 5-HT1BRs underlies the induction of potentiation via CaMKII-dependent phosphorylation of GluA1 at S831 while activation of 5-HT6Rs underlies the maintenance of potentiation via PKA-dependent phosphorylation of GluA1 at S845. Finally, I describe how chronic fluoxetine administration, as would be done with human patients, continuously recruits these signaling molecules to maximally enhance AMPA receptor-mediated synaptic transmission. This modulation of excitatory transmission represents one mechanism by which SSRIs like fluoxetine, and antidepressants in general, may exert their molecular effects and produce a clinical improvement in symptoms associated with depression.en_US
dc.language.isoen_USen_US
dc.subjecttemporoammonicen_US
dc.subject.lcshAntidepressantsen_US
dc.subject.meshHippocampusen_US
dc.subject.meshSerotoninen_US
dc.subject.meshSynaptic Potentialsen_US
dc.titleSerotonin Receptor Signaling Following Selective Serotonin Reuptake Inhibitor Treatment or: How I Learned to Stop Worrying and Love the Agonisten_US
dc.typedissertationen_US
dc.contributor.advisorThompson, Scott M., Ph.D.
dc.contributor.orcid0000-0002-4817-366X
refterms.dateFOA2019-02-19T17:48:11Z


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