Genetic animal models have become an increasingly useful tool in addressing pathophysiological changes in neuropsychiatric disorders at the molecular, synaptic and circuitry levels. Previous genetic and postmortem studies have identified several 14-3-3 isoforms as potential candidate risk genes for schizophrenia. 14-3-3 proteins are a family of homologous proteins involved in many biological processes including signaling, neurite outgrowth and ion channel regulation. In order to investigate the potential associate between 14-3-3 dysregulation and schizophrenia, our lab has created a novel mouse model that addresses the collective function of all 14-3-3 isoforms in the brain. These transgenic mice express a 14-3-3 peptide inhibitor (YFP-difopein) that antagonizes 14-3-3 binding to its endogenous partners and is thus considered a 14-3-3 functional knockout (FKO). We have shown that these 14-3-3 FKO mice exhibit a variety of behavioral and morphological deficits reminiscent of the core endophenotypes of established schizophrenia animal models. This dissertation aims to dissect the molecular pathways and region-specific circuit connections that may be responsible for induction of particular schizophrenic endophenotypes. In Chapter 2, we found that when 14-3-3 proteins are inhibited in the 14-3-3 FKO mice this causes dysregulation of NMDA receptors and actin-signaling at the synapse, possibly leading to deficits in synaptic activity and spine formation. In Chapter 3, we created adeno-associated viruses (AAVs) to determine the brain regions responsible for the circuit control of particular schizophrenic-associated behaviors. We determined that disruption of 14-3-3 function within the dorsal hippocampus alone or the hippocampus and prefrontal cortex together is sufficient to induce schizophrenia-associated behavioral endophenotypes. This effect is most likely due to disturbance in circuit connections within the prefrontal cortex and hippocampus, as restoring 14-3-3 function in both brain regions was necessary in order to attenuate psychomotor disturbances in the 14-3-3 FKO mice. Together, the work presented in this dissertation sheds some light on the role that 14-3-3 plays in the development of psychiatric disorders and provides a framework for future research of schizophrenic models. / A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Spring Semester 2017. / April 3, 2017. / Includes bibliographical references. / Yi Zhou, Professor Directing Dissertation; P. Bryant Chase, University Representative; Mohamed Kabbaj, Committee Member; Yanchang Wang, Committee Member; Zuoxin Wang, Committee Member.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_507665 |
| Contributors | Graham, Kourtney Catherine (authoraut), Zhou, Yi (professor directing dissertation), Chase, P. Bryant (university representative), Kabbaj, Mohamed (committee member), Wang, Yanchang (committee member), Wang, Zuoxin (committee member), Florida State University (degree granting institution), College of Medicine (degree granting college), Department of Biomedical Sciences (degree granting departmentdgg) |
| Publisher | Florida State University, Florida State University |
| Source Sets | Florida State University |
| Language | English, English |
| Detected Language | English |
| Type | Text, text, doctoral thesis |
| Format | 1 online resource (102 pages), computer, application/pdf |
| Rights | This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). The copyright in theses and dissertations completed at Florida State University is held by the students who author them. |
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