Date

2013

Department or Program

Neuroscience

Primary Wellesley Thesis Advisor

Nancy H. Kolodny

Additional Advisor(s)

Deborah Bauer

Additional Advisor

Mike Wiest

Additional Advisor

Brandon Abbs

Abstract

Schizophrenia plagues approximately 1% of the world’s population. This chronic brain disorder is marked by behavioral, cognitive and social abnormalities. Studies on the brain pathophysiology of schizophrenia have also found predominant structural and neurochemical aberrations. While no single cause of the disorder has been identified; environmental, genetic and epigenetic factors have been implicated. This thesis is both an investigation of the genetically modified GCPII+/- mouse model as well as the groundwork for the implementation of diffusion tensor imaging and an updated epigenetic mouse model. Groundwork for the updated mouse model included rodent stereotactic surgery design to ultimately induce epigenetic dysregulation with hopes of better modeling the variable development and symptomology of schizophrenia. The primary GCPII+/- mouse model sustains decreased expression of the enzyme glutamate carboxypeptidase II (GCPII) integral for glutamate synthesis in order to diminish glutamatergic N-methyl-d-aspartate (NMDA) receptor activity. Magnetic resonance imaging, spectroscopy and a social task were used to test for the abnormalities that GCPII+/- might exhibit. Tests were conducted on both mice heterozygous for GCPII+/-mutation (HET) and their wild-type (WT) counterparts at numerous ages corresponding to mouse adolescence and adulthood. We hypothesized that HET mice would exhibit differential volume of brain structures and neurometabolites compared to WT mice, as well as social deficiency. Magnetic resonance imaging (MRI) and spectroscopy (MRS) data were obtained on post natal days (PND) 35/36, 49/50 and 63/64 and social task data were obtained between PND 114 and 117. Both MRI and MRS data revealed sex differences. HET males exhibited more structural abnormalities than HET females with greater hippocampal asymmetry and decreased right hippocampal volume compared to WT males. Ventricular enlargement or asymmetry was not reported in HET males nor females. HET females exhibited more abnormalities in neurometabolite levels with elevated levels of choline and glutamate, as well as diminished levels of N-acetylaspartate and N-acetylaspartylglutamate compared to WT females. Behavioral data found that both HET males and females exhibit a social deficit. Each sets of results mirrored findings in MRI and MRS studies on schizophrenia as well as characteristic social abnormalities. Data serve as a testament to the promise of the GCPII+/- mouse model but are also indicative of the model’s shortcomings.

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