Examining a GCPII+/-/rAAV9 Genetic and Epigenetic Mouse Model of Schizophrenia using Magnetic Resonance

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 (MRI) to acquire coronal images of the brain for volumetric analysis, Magnetic Resonance Spectroscopy (MRS) 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. Heterozygote (HET) vs. wild type (WT) male and female mice with viral injections, saline injections, or no injections were examined with MRI and MRS on postnatal days (PND) 35/36, 49/50, and 63/64, while DTI experiments were conducted on PND 28/29, 42/43, and 56/57. MRI data revealed increased cerebellum volumes in HET males compared to WT controls, though few other neuroanatomical changes reflective of schizophrenia in humans (lateral ventricular enlargement and hippocampal reduction) were observed. MRS experiments found neurochemical abnormalities in each metabolite examined, most notably a reduction in Glx/Cr in HET males at later time points, as well as a significant decrease in (NAA+NAAG)/Cr in both HET males and females. These trends may mirror changes observed in human schizophrenia patients. DTI data did …