• Characterizing enhancer-driven transcriptional networks in schizophrenia

      Casella, Alex; Ament, Seth A. (2021)
      Genetic studies of schizophrenia have demonstrated that more than 90% of genetic risk is confined to non-coding portions of the genome. Advances in chromatin state prediction and chromatin accessibility assays have enabled us to better characterize the genomic features making up these regions and annotate genetic risk to these elements. The focus of this dissertation is to understand the role that tissue- and cell type- specific regulatory elements and the transcription factors that bind them play in risk for schizophrenia. I hypothesized that enhancer-based transcription factor-target networks that direct neuronal development are disrupted in schizophrenia. To test this hypothesis, I used high-quality chromatin state predictions in both the developing and the adult brain to develop a framework for testing enhancer properties for association with genetic risk. Any enhancer-level annotation can be used in this type of test, including transcription factor binding counts and chromosomal contact information. I first described and validated an atlas of transcription factor binding sites across multiple human tissue, including the brain. I then used this atlas to show that neurodevelopmental transcription factors and target genes are most associated with risk for developing schizophrenia.
    • Cognition Following Prenatal Stress and/or Disruption of Neuregulin-1 Gene; Implications for Schizophrenia

      Taylor, Adam Ryan; Koenig, James I. (2011)
      Schizophrenia is a severe, chronic and disablilitating disease, affecting nearly one percent of the population. Symptoms consist of positive (hallucination, delusions), negative (anhedonia, social withdrawal) and cognitive (memory impairments, attentional deficits). Cognitive symptoms are considered to be a core feature, and contribute greatly to loss of function. Environmental insults, such as prenatal stress, have been shown to increase risk for schizophrenia. In addition, genetic studies have shown that certain genes, such as Neuregulin-1 (NRG1), are consistently associated with schizophrenia. Interactions between genetic vulnerabilities and environmental factors are also considered to be important in the development of schizophrenia. Here, using an animal model of repeated variable prenatal stress (RVPS), we have shown that animals exposed to RVPS have deficits in spatial learning and memory in the Morris water maze, deficits in working memory in a spatial/visual object discrimination task, and long-term memory deficits. Utilizing a rat preparation with disruption of the neuregulin-1 gene, which leads to decreased NRG1 mRNA and protein in the brain, we have found no deficit in the spatial learning version of the Morris water maze, but we do see learning impairments in a discrimination task with both visual and spatial components. Finally, we were not able to show a substantial effect of a gene X environment interaction between RVPS and Nrg1 disruption. Our results indicate that both prenatal stress and disruption of the neuregulin-1 gene, each risk factors for schizophrenia, result in specific deficits in learning and memory. These deficits are also similar to some cognitive impairments in schizophrenia, indicating our manipulations may be a factor in those symptoms of the disease.
    • Dominant-Negative Disrupted in Schizophrenia 1 Alters the Dopaminergic Modulation of Excitatory-Inhibitory Balance in the Prefrontal Cortex

      Cardarelli, Ross Andrew; O'Donnell, Patricio (2013)
      Dysfunction of inhibitory cells, especially of fast-spiking interneurons within the prefrontal cortex, is a convergent phenotype existing in patients with schizophrenia and within animal models of the disorder. Despite a large amount of research into the molecular and behavioral consequences of different manipulations, the electrophysiological phenotype of cells within relevant brain areas including the prefrontal cortex remains underexplored. In this dissertation, I utilized whole cell recordings to first differentiate between classes of neurons in the normal-developing prefrontal cortex and then discerned the pattern of their modulation by dopamine receptor D2 agonists. I then contrasted this normal, late-maturing phenotype with that in mice carrying a truncated human disrupted in schizophrenia 1 (DISC1) allele. I will show that fast-spiking interneurons in mice expressing mutated DISC1 lose their normal electrophysiological phenotype including a failure to attain a normal adult firing profile and dopamine response, and conclude that early-life gene disruption can result in electrophysiological dysfunction of GABAergic interneurons.
    • Effect of Two Nonsynonymous Variants of the GABAergic Enzyme Genes, GAD1 and ALDH5A1, on Processing Speed in Healthy Controls and Schizophrenia Patients

      Whittaker, Clare; Hong, Elliot (2013)
      Schizophrenia has been associated with altered GABAergic function in the brain. Gamma aminobutyric acid (GABA) is synthesized by GAD67 (glutamate decarboxylase weighing 67kDa) and GAD65, encoded in GAD1 and GAD2 genes, respectively, and degraded by succinic semialdehyde dehydrogenase (SSADH) encoded in ALDH5A1. Previous research suggests that individuals with schizophrenia have an elevated level of GABA and also have a processing speed deficit. We hypothesized that the GAD1 variant, Arg532Gln, and the ALDH5A1 variant, His180Tyr, could alter these enzymes' functions and be associated with the processing speed deficit seen in individuals with schizophrenia. The ALDH5A1 variant His180Tyr is known to reduce the enzyme function of SSADH; while the effect of the GAD1 variant, Arg532Gln is currently unknown. The Digit Symbol coding task was used to measure processing speed in 153 healthy controls and 158 patients with schizophrenia. Both groups were genotyped for GAD1 Arg532Gln and ALDH5A1 His180Tyr missense SNPs. Using this clinical information, we attempted to determine the amount of variation in Digit Symbol coding score between patients and controls that could be explained by these GAD1 and ALDH5A1 SNPs. Case-control analysis was also performed to determine if either SNP was associated with a diagnosis of schizophrenia. A GAD67 functional enzyme assay was developed to determine if Arg532Gln is a functional mutation and therefore partially responsible for the processing speed deficit present in many individuals with schizophrenia. Results showed that GAD1 Arg532Gln was significantly associated with reduced digit symbol score in the control group (R2=4.9%, p=0.006) and the schizophrenic group (R2=3.7%, p=0.015); however, only the association with the control population remained significant after the Bonferroni correction. The functional GAD67 enzyme assay showed that Arg532Gln results in increased GABA production. ALDH5A1 His180Tyr was also significantly associated with reduced digit symbol score in the control group (R2=5.6%, p=0.003), but not the schizophrenic group (R2=1.5%, p=0.131). Neither SNP was associated with schizophrenia in either the Caucasian or African American population. In conclusion, the GAD1 and ALDH5A1 variants are not significantly associated with schizophrenia, but are significantly associated with processing speed. We also found that Arg532Gln results in increased GAD67 activity.
    • Predictors of quality of life in patients with schizophrenia

      Raymond, Roberta Ann; McCrone, Susan Hillman (1998)
      Schizophrenia is a complex syndrome that has far reaching effect on the lives of the patients afflicted with the disease. It is estimated that 1 million people in the United States carry a diagnosis of schizophrenia. An individual with the diagnosis of schizophrenia can expect to have an impoverished quality of life. Quality of life is a multidimensional concept that includes the physical, social, and emotional health of an individual. This study, using secondary data analysis, explored the demographic and clinical indicators that could be predictors of quality of life for patients with schizophrenia. Subjects in this study were patients with schizophrenia who were receiving treatment and participating in research studies in an outpatient research clinic. Instruments used in this study were the Brief Psychiatric Rating Scale, the Schedule for the Deficit Syndrome, and the Quality of Life Scale. The data were analyzed using multiple regression analysis. Significant predictors of quality of life were found to be the demographic indicator of socioeconomic status, the clinical indicators of conceptual disorganization and the classification of the deficit syndrome.
    • Teenage Brains on Pot: Adolescent Cannabinoid Exposure to Mice and Maturation of Cortical Functions

      Raver, Sylvina Mullins; Keller, Asaf (2014)
      Regular use of marijuana during adolescence -- but not adulthood -- permanently impairs cognitive functions, and significantly elevates the risk for developing severe psychiatric diseases, such as schizophrenia, in some users. This vulnerable adolescent period coincides with the emergence of synchronous, network activity in the neocortex, termed cortical oscillations, as well as the anatomical and physiological maturation of the neural networks, neurotransmitter systems, and the endocannabinoid (eCB) system that shape oscillations. Cortical oscillations are implicated in cognitive and sensory processing, and are abnormal in patients with schizophrenia, in which these functions are impaired. We therefore proposed a link between adolescent use of marijuana, and abnormal cortical network activity in adulthood. Specifically, we hypothesized that repeated cannabinoid administration to adolescent mice would permanently alter cortical oscillations and related cognitive behaviors in adult animals. We tested this hypothesis by administering cannabinoid receptor ligands to adolescent mice, and recording oscillations both in vitro from isolated cortical preparations, and in vivo from intact, behaving mice once they reached adulthood. We find that chronic cannabinoid exposure to adolescent, but not adult animals, persistently suppresses pharmacologically-evoked cortical oscillations in vitro, preferentially in rostral neocortical areas that are less developed at the time of drug exposure. In awake, behaving adult mice, chronic exposure to cannabinoids in adolescence attenuates pharmacologically-evoked cortical oscillations, impairs working memory, and alters oscillations associated with cognitive behaviors. We reveal that attenuation of cortical oscillations in adulthood by a shorter-period of cannabinoid exposure during early adolescence, or by chronic exposure to the primary active ingredient in marijuana, Δ9 THC, is mediated by the cannabinoid-1 receptor (CB1R), and can be reversed with a CB1R antagonist. However, chronic exposure to a more potent cannabinoid receptor agonist cannot be reversed by chronic exposure to cannabinoid receptor antagonists, as antagonists also persistently attenuate oscillations in adulthood when administered alone. These data support the hypothesis that marijuana use in adolescence persistently alters synchronous activity in cortical networks in adulthood, and serve as a novel link between early cannabis use and alterations in cortical network activity implicated in cognitive processing and psychiatric disease.