THE ROLE OF CA2+/CALMODULIN-DEPENDENT KINASE II
IN NORMAL AND ABNORMAL EARLY POSTNATAL DEVELOPMENT
RICHARD GUSTIN
Dissertation under the direction of Professor Roger J. Colbran
Ca2+/calmodulin-dependent kinase II (CaMKII) is known to play important roles in mechanisms underlying molecular memory and has been shown to be misregulated in adult rodent models of altered learning and memory. However, the regulation and role of CaMKII during development in vivo is poorly understood. In this dissertation I have taken advantage of three rodent models of genetic (Angelman Syndrome and CaMKIIα-Thr286Ala knock-in) and environmental (Early-Life Stress) perturbation to assess the role of CaMKII during development. I was able to show that maternal imprinting of UBE3A in a mouse model of Angelman Syndrome (AS) was not brain region specific, but extended throughout the brain as well as in peripheral tissues, presumably contributing to the broad neurological and peripheral phenotypes of the AS mice and human AS patents. Studies with this AS mouse model led me to hypothesize that the previously reported CaMKII misregulation was potentially due to deficient maternal care provided by AS dams. This led to the adoption of an early-life stress (ES) paradigm in mice, where I was able to establish that CaMKII was misregulated in the ES mice. The ES animals also showed synaptic transmission deficits lasting into adulthood that may account for some of the previously reported behavioral deficits in this model. Phosphorylation of CaMKIIα at Thr286 renders the kinase autonomously active. To specifically test the role of CaMKIIα-Thr286 phosphorylation during development I used a transgenic mouse model, CaMKIIα-Thr286Ala knock-in mouse, where I was able to identify an early-life novel object recognition deficit associated with CaMKII misregulation and altered localization. Overall, I determined that genetic and environmental perturbations that alter CaMKIIα regulation during development also alter synaptic transmission and learning and memory long-term. Furthermore, I have shown that altering the ratio of specific CaMKII isoforms that make up the holoenzyme is able to cause differential association with protein complexes that can have significant effects on learning and memory.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-06282010-154107 |
| Date | 29 June 2010 |
| Creators | Gustin, Richard Michael |
| Contributors | Roger J. Colbran, Vsevolod Gurevich, Joey V. Barnett, Pat Levitt, David Zald |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu//available/etd-06282010-154107/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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