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Behavioral and molecular correlates of major depression in mice lacking the serotonin transporter

Joeyen-Waldorf, Jennifer (2010) Behavioral and molecular correlates of major depression in mice lacking the serotonin transporter. Master's Thesis, University of Pittsburgh. (Unpublished)

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Major depressive disorder (MDD) is responsive to serotonin transporter reuptake inhibitors (SSRIs), and a functional polymorphism in the serotonin transporter (SERT) putative promoter region impacts vulnerability to develop MDD. Paradoxically, mice lacking SERT (knock-out; SERT-KO) display an increased anxiety-like phenotype, which has been demonstrated to have developmental origins; however, the extent to which systems adaptations that have occurred in SERT-KO mice recapitulates a broader anxious depressive-like phenotype at the behavioral and molecular levels is not known. We investigated SERT-KO in a panel of behavioral tests, and analyzed WT and KO gene expression in amygdala (AMY) and cingulate cortex (CC) by microarray. We then compared the SERT-KO gene expression results to human MDD and Control microarray in AMY and anterior cingulate cortex (ACC), areas shown to be functionally, structurally and molecularly affected in MDD. Gene expression changes were confirmed by real-time quantitative polymerase chain reaction (qPCR). RESULTS: SERT-KO behaviors across several tests denote a robust anxious depressive-like syndrome, which is reminiscent of the human MDD syndrome. Some gene expression changes were conserved between mouse and human in AMY and ACC/CC as measured by microarray (29 genes; 19 genes), and a subset were selected for qPCR validation. Differential gene expression confirmed by qPCR in both mouse and human (2 genes in AMY) included an upregulation in AMY of adenylate cyclase VII (ADCY7), a gene previously implicated in MDD. Increased expression of two genes that display significant coregulation in mouse and human suggests the recruitment of a conserved functional unit related to cyclic adenosine monophosphate (cAMP) signaling, a signal transduction pathway implicated in MDD. CONCLUSIONS: The SERT-KO mouse recapitulates behavioral and selected molecular features of a rodent syndrome homologous to human MDD. Therefore, it provides a useful model for investigating molecular mechanisms in AMY which are relevant to the pathology of MDD. These results support altered cAMP signaling pathway as a cross-species conserved feature of the pathophysiology of MDD.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairLewis, Davidlewisda@upmc.eduTNPLEWIS
Committee MemberThiels, Eddathiels@pitt.eduTHIELS
Committee MemberSibille,
Committee MemberRinaman, Lindarinaman@pitt.eduRINAMAN
Date: 8 June 2010
Date Type: Completion
Defense Date: 19 April 2010
Approval Date: 8 June 2010
Submission Date: 21 April 2010
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Neuroscience
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: adenylate cyclase; animal model; depression; MDD; serotonin transporter
Other ID:, etd-04212010-135459
Date Deposited: 10 Nov 2011 19:40
Last Modified: 19 Dec 2016 14:35


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