Date

2015

Department or Program

Chemistry

Primary Wellesley Thesis Advisor

Nancy H. Kolodny

Abstract

Schizophrenia is a chronic brain disorder that affects approximately 24 million people worldwide, with about 50% of those affected by the disorder not receiving care (World Health Organization, 2013). Individuals with schizophrenia often exhibit abnormalities in behavior, cognition, and sociability. While the exact cause of the disorder remains unknown, environmental, genetic, and epigenetic factors have been implicated in its onset. This thesis seeks to validate the GCPII+/-/rAAV9 genetic and epigenetic mouse model of schizophrenia by observing whether it induces neurochemical, neurostructural, and behavioral abnormalities that mimic those observed in human patients. Previous studies in our laboratory explored a GCPII+/- mouse model of schizophrenia in which the folate 1 gene, necessary for the production of glutamate carboxypeptidase II (GCPII), was knocked out. Thus, these mice were hypothesized to model glutamate receptor dysfunction by exhibiting altered levels of the neurotransmitter glutamate. Past studies using Magnetic Resonance Imaging to acquire coronal images of the brain for volumetric analysis, Magnetic Resonance Spectroscopy to evaluate neurometabolite levels, and a behavioral paradigm to examine social tendencies demonstrated that the GCPII+/- model exhibited some, but not all, of the abnormalities associated with schizophrenia in humans. In order to induce epigenetic dysregulation and modify the previous model, a recombinant adeno-associated virus 9 (rAAV9) carrying histone deacetylase enzyme 1 cDNA was introduced into postnatal day (PND) 1 GCPII+/- mice. To further characterize this modified model, Diffusion Tensor Imaging (DTI) was used to visualize abnormalities in white matter connectivity in the brain. This thesis offers an initial analysis of the updated genetic and epigenetic mouse model of schizophrenia as well as an overview of the potential for DTI to be used in future studies.

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