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dc.contributor.advisorMuma, Nancy A
dc.contributor.authorMi, Zhen
dc.date.accessioned2016-10-13T19:01:57Z
dc.date.available2016-10-13T19:01:57Z
dc.date.issued2015-12-31
dc.date.submitted2015
dc.identifier.otherhttp://dissertations.umi.com/ku:14306
dc.identifier.urihttp://hdl.handle.net/1808/21731
dc.description.abstractDendritic spines are small membranous protrusions from the dendrites of neuron, which are thought to serve as basic units of synaptic transmission, learning and memory. Disruptions in dendritic spine shape, size or number are associated with many brain diseases. Mounting evidence suggests that serotonin 2A (5-HT2A) receptors, the most abundant serotonin receptors in the prefrontal cortex, are involved in the regulation of dendritic spines. It has been suggested that both agonists (such as DOI) and antagonists (such as atypical antipsychotics) of 5-HT2A receptors can modulate different aspects of dendritic spines, however, the underlying mechanisms still remains unknown. In this dissertation, mechanisms underlying regulation of dendritic spines by both agonists and antagonists of 5-HT2A receptors are extensively studied and presented. I hypothesize that 5-HT2A receptor agonist regulate dendritic spines via transglutaminase- (TGase) catalyzed serotonylation of small G protein of the Rho family, whereas atypical antipsychotics change dendritic spines via activation of the Janus Kinase 2 (JAK2) signaling pathway. In the first study, the mechanisms and the functional consequences of 5-HT2A receptor-induced serotonylation of small G proteins of the Rho family were investigated in primary rat cortical neurons. Stimulation of 5-HT2A/2C receptors caused TGase-mediated transamidation and activation of Rac1 and Cdc42, but not RhoA, in both A1A1v cells and rat primary cortical culture. DOI-induced Rac1 transamidation occurs at Q61 in A1A1v cells, as demonstrated by site-directed mutagenesis at Q61 of Rac1. Furthermore, our findings were extended from 5-HT2A/2C receptors to another Gαq/11-coupled receptor, muscarinic acetylcholine receptors. In addition, stimulation of 5-HT2A/2C receptors by DOI leads to a transient dendritic spine enlargement, which was blocked by TGase inhibitor cystamine, suggesting 5-HT2A/2C receptors-induced transamidation of Rac1 and Cdc42 is involved in the regulation of dendritic spines by 5-HT2A/2C receptors. In the second study, to study the role of JAK2/ STAT pathway in the regulation of dendritic spines, Sprague-Dawley rats were pretreated with the JAK2 inhibitor AG490 or vehicle, followed by administration with olanzapine or vehicle daily for seven days. Microarray analysis of prefrontal cortices showed that 205 genes were significantly changed by AG490, olanzapine or the combination of both drugs compared to the controls. 92 of the 205 genes are changed by olanzapine via JAK2 signaling pathway. These genes are involved in the etiology of schizophrenia, neuronal signal transduction, neuronal growth factor, metabolism and energy, and synaptic plasticity. mRNA and protein levels of these genes were verified using real-time qPCR, western blot and the enzyme-linked immunosorbent assay (ELISA). Investigation on dendritic morphology shows that treatment with olanzapine induced a maturation in dendritic spines via both JAK2 dependent and independent pathways.
dc.format.extent148 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsCopyright held by the author.
dc.subjectNeurosciences
dc.subjectMolecular biology
dc.subjectatypical antipsychotics
dc.subjectdendritic spines
dc.subjectJAK/STAT
dc.subjectserotonin 2A receptor
dc.subjectsmall G protein of the Rho family
dc.subjecttransamidation
dc.titleREGULATION OF DENDRITIC SPINES BY 5-HT2A RECEPTOR SIGNALING PATHWAYS
dc.typeDissertation
dc.contributor.cmtememberMuma, Nancy A
dc.contributor.cmtememberBortolato, Marco
dc.contributor.cmtememberWang, Xinkun
dc.contributor.cmtememberLundquist, Erik A
dc.contributor.cmtememberLi, Qian
dc.thesis.degreeDisciplinePharmacology & Toxicology
dc.thesis.degreeLevelPh.D.
dc.rights.accessrightsopenAccess


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