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Title page for ETD etd-06282010-154107


Type of Document Dissertation
Author Gustin, Richard Michael
URN etd-06282010-154107
Title The role of Ca2+/calmodulin-dependent kinase II in normal and abnormal early postnatal development
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Vsevolod Gurevich Committee Chair
David Zald Committee Member
Joey V. Barnett Committee Member
Pat Levitt Committee Member
Roger J. Colbran Committee Member
Keywords
  • Angelman syndrome
  • Early-life stress
  • transgenic mouse
  • CaMKII
Date of Defense 2010-06-15
Availability unrestricted
Abstract
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.

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