Despite a prevailing paradigm that emphasizes an interaction of vulnerability and stress to account for the etiology of schizophrenia, diathesis—stress models of subsequent course and outcome of this disorder are rare. Even the simpler stress— process model, where the influence of stressors is mediated by supportive social relationships, has received little attention in studies of the course of schizophrenia. The objective of this study was to assess the following components of a diathesis—stress model as they predict the five-year outcome of first-episode schizophrenia: (1) stressful life events; (2) supportive social relationships; (3) brain lateral ventricle size; and (4) smooth pursuit eye movements. As part of the Greater Vancouver M.A.P. Project, we recruited first-episode DSM-III schizophrenia and affective psychosis patients. At intake to the study, their social relationships, smooth pursuit eye movement function, and brain ventricle size were assessed. Life events in the previous year were measured at intake; events over the following 18 months were assessed in two later interviews. Five years later we assessed outcome, using a global rating of social and occupational functioning. Descriptive results showed substantial variability within the schizophrenia group at intake and outcome. The trajectory of adaptive functioning over time was remarkably similar for the schizophrenic and affective psychosis groups. Of the four hypothesized predictors, only social relationships were associated (p=.O3) with five—year outcome. The number of life events was not associated with five—year outcome, nor was either of the biological risk factors. As a result, the predictor variables could not be combined in either a stress—process model or a vulnerability—stress model of the course of schizophrenia. That social relationship variables are associated with five-year outcome supports earlier findings regarding 18-month outcome, including the differing predictive roles for family and nonfamily relationships. The absence of hypothesized results for the life events data probably indicates that too much time had passed between outcome and the events as measured. Finally, that brain ventricle size and eye-movement dysfunction predict 18-month but not five—year outcome may indicate that impairment due to biological factors is expressed only in the early stages of schizophrenia.

Despite a prevailing paradigm that emphasizes an interaction of vulnerability and stress to account for the etiology of schizophrenia, diathesis—stress models of subsequent course and outcome of this disorder are rare. Even the simpler stress— process model, where the influence of stressors is mediated by supportive social relationships, has received little attention in studies of the course of schizophrenia. The objective of this study was to assess the following components of a diathesis—stress model as they predict the five-year outcome of first-episode schizophrenia: (1) stressful life events; (2) supportive social relationships; (3) brain lateral ventricle size; and (4) smooth pursuit eye movements. As part of the Greater Vancouver M.A.P. Project, we recruited first-episode DSM-III schizophrenia and affective psychosis patients. At intake to the study, their social relationships, smooth pursuit eye movement function, and brain ventricle size were assessed. Life events in the previous year were measured at intake; events over the following 18 months were assessed in two later interviews. Five years later we assessed outcome, using a global rating of social and occupational functioning. Descriptive results showed substantial variability within the schizophrenia group at intake and outcome. The trajectory of adaptive functioning over time was remarkably similar for the schizophrenic and affective psychosis groups. Of the four hypothesized predictors, only social relationships were associated (p=.O3) with five—year outcome. The number of life events was not associated with five—year outcome, nor was either of the biological risk factors. As a result, the predictor variables could not be combined in either a stress—process model or a vulnerability—stress model of the course of schizophrenia. That social relationship variables are associated with five-year outcome supports earlier findings regarding 18-month outcome, including the differing predictive roles for family and nonfamily relationships. The absence of hypothesized results for the life events data probably indicates that too much time had passed between outcome and the events as measured. Finally, that brain ventricle size and eye-movement dysfunction predict 18-month but not five—year outcome may indicate that impairment due to biological factors is expressed only in the early stages of schizophrenia. / Arts, Faculty of / Psychology, Department of / Graduate

Amino acids and other ninhydrin-positive compounds were measured in post-mortem thalamus from 25 Huntington's choreics, 10 schizophrenics, 5 schizophrenic-like psychotics, and 23 controls dying without neurological disease. Gamma-aminobutyric acid (GABA) was significantly reduced in choreic thalami, in accord with deficiencies found in other brain regions choreics (Perry et al., 1973a,b). GABA was also significantly reduced in schizophrenic thalami, suggesting a biochemical link between these two diseases, and supporting the hypothesis of a defect in the GABA system in schizophrenia (Roberts, 1972). Homocarnosine, a GABA-containing dipeptide, was also low in choreic and 9 out of 10 schizophrenic thalami. One schizophrenic had extremely high homocarnosine. Glycerophosphoethanolamine was significantly elevated in Huntington's choreics, but not in schizophrenics. A number of other variables were considered for their potential influence on amino acid concentrations in thalamus. The majority of amino acids were found to rise in a significantly linear fashion in the interval 3 to 49 hours post-mortem, although other models might have described the change better. GABA, ornithine, histidine and tyrosine were found to decrease significantly with increasing age between 21 and 80 years, in controls. The effects of pre-mortem hypoxia, regional variation within the thalamus, and neuroleptic drug treatment could not be rigorously tested with these data. Neuroleptics were unlikely to have been the cause of group differences in GABA concentration, since they failed to deplete GABA in brain of chronically treated rats. On the other hand, bronchopneumonia and other causes of pre-mortem hypoxia could not be ruled out as potential contributers to reduced GABA in thalamus. / Medicine, Faculty of / Medical Genetics, Department of / Graduate

Cognitive impairments are a hallmark of many, if not all, psychiatric disorders. They include deficits in working memory, attention, and cognitive flexibility. The prefrontal cortex (PFC) is essential for these cognitive functions and has been implicated in psychiatric disorders, including schizophrenia. The PFC receives reciprocal inputs from the thalamus, and this thalamo-PFC circuitry supports cognition. In patients with schizophrenia, who have impaired cognitive functioning, thalamo-PFC connectivity is disrupted. This finding is also seen in adolescents at high risk for the disorder, even before diagnosis.While impaired cortical maturation has been postulated as a mechanism in the etiology of schizophrenia, the postnatal development of thalamo-PFC circuitry is still poorly understood. In sensory cortex, activity relayed by the thalamus during a postnatal sensitive period is essential for proper cortical maturation. However, whether thalamic activity also shapes maturation of the PFC is unknown. Here, I will present evidence to support the hypothesis that adolescence represents a sensitive period, during which the PFC is susceptible to transient perturbations in thalamic input activity, resulting in persistent changes in circuitry. In Chapter 1, I present the existing literature on schizophrenia and our current understanding of its etiology. I then review the structure and connectivity of the PFC and its inputs, including the thalamus, in the context of schizophrenia and cognition. Next, I discuss the role of adolescence in the development of these structures and circuits. Finally, I introduce the concept of sensitive periods and outline the hypothesis that a similar process may occur in the context of the adolescent development of thalamo-PFC circuitry. To assess cognitive functioning in mouse models, I developed an operant-based working memory task. In Chapter 2, I describe this newly developed task and demonstrate that behavioral performance in the task is susceptible to PFC lesions. Thus, the task offers a new approach to studying PFC cognitive function. In Chapter 3, I discuss work done to address the hypothesis of adolescence as a sensitive period in the development of thalamo-PFC circuitry. I established an approach whereby I can transiently reduce activity in the thalamus during specific time windows. In this way, I compared the persistent effects of transient thalamic inhibition during adolescence and adulthood. I found that adolescent thalamic inhibition causes long-lasting deficits in cognitive behavioral performance, including the operant-based working memory task described in Chapter 2 and a cognitive flexibility task, decreased PFC cellular excitability, and reduced thalamo-PFC projection density. Meanwhile, adult thalamic inhibition has no persistent consequences on behavior or PFC excitability. Adolescent thalamic inhibition also results in disrupted PFC cellular cross-correlations and task outcome encoding during the cognitive flexibility task. Strikingly, exciting the thalamus in adulthood during the behavioral task rescues PFC cross-correlations, task outcome encoding, and the cognitive deficit. These data support the hypothesis that adolescence is a sensitive period in thalamo-PFC circuit maturation as adolescent thalamic inhibition has long-lasting consequences on PFC circuitry, while adult thalamic inhibition has no persistent effects. Moreover, these results highlight the role of the thalamus as a non-specific facilitator of PFC activity, expanding our understanding of this thalamic function to additional cognitive contexts. By supporting PFC network activity, boosting thalamic activity provides a potential therapeutic strategy for rescuing cognitive deficits in neurodevelopmental disorders. Finally, in Chapter 4, I conclude with a general discussion. I highlight major take-aways from this work as well as next steps in our exploration of these crucial neural circuits. Together, the findings outlined here offer new promise for early diagnosis and treatment options for patients with cognitive impairments and psychiatric disorders.

Schizophrenia is a disabling psychiatric and neurodevelopmental disorder that represents a tremendous public health burden. Despite the inroads made in the treatment of its symptoms, understanding its etiology and pathophysiology remains challenging due to the genetic heterogeneity of the disease and the corresponding complexity of the neural systems which it affects. In recent years, the development of next generation sequencing and substantial progress in the field of psychiatric genetics have revealed the important role of individually rare but collectively common heritable and de novo mutations (DNMs) in the complex genetic architecture of schizophrenia. Previously, we had identified SETD1A encoding a histone methyltransferase, as a high-risk gene for schizophrenia, which has been confirmed extensively through follow-up meta-analyses. This discovery emphasized the important role that neural gene regulation plays in the coordination of complex cognitive processes. However, it is unclear how to translate a ubiquitous molecular process such as chromatin modification into a mechanistic and disease-specific insight. Our previous comprehensive analysis of mutant mice carrying a loss of function (LoF) allele in the Setd1a orthologue uncovered the role of SETD1A in gene regulation, neuronal architecture, synaptic plasticity, neuronal ensemble activity and cognitive function and showed that neurocognitive deficits that derive from Setd1a deficiency can be reversed by pharmacological interventions during adulthood. Our previous ChIP-Seq analysis showed a striking overlap between SETD1A, MEF2, and LSD1 targets at enhancers in the prefrontal cortex (PFC). Since MEF2 is an activity dependent transcription factor, we hypothesized that SETD1A may also modulate activity-dependent gene expression in the brain. To elucidate the effects of Setd1a deficiency on activity-dependent transcription, we established an in vitro neuronal activity dependent gene (ADG) expression assay and identified genes modulated by neuronal activity using ChIP-Seq and RNA-Seq assays. We found a remarkable overlap of a dynamic pattern of activity-dependent recruitment of SETD1A, LSD1 and MEF2 to enhancers of ADGs. Our results showed Setd1a deficiency affects transcription in an activity-dependent manner and transcriptional alteration induced by Setd1a deficiency under neuronal activation can be attenuated by inhibition of LSD1 activity. In addition, we investigated how SETD1A modulates MEF2 transactivation activity by performing luciferase assays. Our results suggest that SETD1A represses MEF2 activity but the repression is unlikely to be mediated by lysine methylation. We also performed behavioral analyses of Setd1a+/- mice and found that the social behavior and social memory were impaired in female Setd1a+/- mice but remained intact in male Setd1a+/- mice. Ultimately, future work is underway to analyze the targets of SETD1A, which in turn could lead to the development of therapeutic strategies to reverse the progression of schizophrenia.

Over the past 20 years, Genome-Wide Association Studies (GWAS) have identified thousands of variants in the genome linked to genetic diseases. However, these associations often reveal little about underlying genetic etiology, which for many phenotypes is thought to be highly heterogeneous. This work investigates statistical methods to move beyond conventional GWAS methods to both improve estimation of associations and to extract additional etiological insights from known associations, with a focus on schizophrenia. This thesis addresses the above aim through three primary topics: First, we describe DNA.Land, a web platform to crowdsource the collection of genomic data with user consent and active participation, thereby rapidly increasing sample sizes and power required for GWAS. Second, we describe methods to characterize the latent genomic contributors to heterogeneity in GWAS phenotypes. We develop a Z-score test to detect heterogeneity using correlations between variants among affected individuals, and we develop a contrastive tensor decomposition to explicitly characterize subtype-specific SNP effects independently of confounding heterogeneity such as ancestry. Using these methods we provide evidence of significant heterogeneity in GWAS cohorts for schizophrenia. Lastly, a major avenue of investigation beyond GWAS is identifying the genes through which associated SNPs mechanistically affect the presentation of phenotypes. We develop a method to improve estimation of expression quantitative trait loci by joint inference over gene expression reference data and GWAS data, incorporating insights from the liability threshold model. These methods will advance ongoing efforts to explain the complex etiology of genetic diseases as well as improve the accuracy of disease prediction models based on these insights.

Gender has long been considered an important factor in uncovering the etiology of schizophrenia. There is now strong evidence that gender is related to the age at onset of psychotic symptoms and somewhat weaker evidence of gender differences in other aspects of schizophrenia, such as clinical and functional outcomes. Simultaneously, there is growing evidence that age at onset itself is an important prognostic factor. This dissertation seeks to investigate the complex relationship between gender, age at onset, and outcomes of schizophrenia spectrum disorders, in light of two main mechanisms, estrogen protection and psychosocial development. The estrogen protection hypothesis posits that estrogen has antipsychotic effects that result in a later age at onset and more favorable outcomes for pre-menopausal women compared with men with onset at the same age. When women lose estrogen protection around menopause, they may develop a more severe illness. The psychosocial development hypothesis posits that women who have later onset due to estrogen protection have more time to develop psychosocial resources that improve their role functioning later in life. In Chapter 2, a systematic literature review was conducted on the relationship between gender and age at onset of schizophrenia spectrum disorders in determining functional outcomes. There was some support for the psychosocial development hypothesis where age at onset mediates the relationship between gender and functional outcomes. Three studies were identified that conducted formal mediation analyses and used minimum criteria to detect mediation in the remaining studies. Together, these findings suggest that women have better functioning outcomes than men, by virtue of having later illness onset. Chapters 3 & 4 utilized a nationally representative sample of people with schizophrenia spectrum disorders in China to further examine the relationship between gender, age at onset, and other illness outcomes. Unlike many studies in the current literature, this dataset included people who had never sought formal treatment, providing a unique opportunity to explore the possibility of selection bias in other studies that primarily recruit participants from treatment settings. Furthermore, the majority of schizophrenia research has been conducted in high-income countries, and these data from China could provide some important insights from a low- to middle-income country. In Chapter 3, finite mixture techniques were used to model the entire distribution of age at onset as a function of gender and family history, taking into account any clustering patterns of observations. The analysis identified an early-onset group characterized by men and those with a family history, a mid-onset group characterized by both men and women without a family history, and a late-onset group characterized by women without a family history. Distinguishing between these groups showed that gender and family history are indeed robust predictors of age at onset. Chapter 4 investigated a) the interaction between gender and age at onset in producing clinical outcomes and b) the mediating effect of age at onset in the relationship between gender and role functioning outcomes. This study did not find evidence of interaction between gender and age at onset in producing clinical outcomes. It did find that women’s increased probability of marrying was mediated by a later age at onset. Overall, the results of this dissertation provide even further support of the well-established relationship between gender and age at onset. However, applying the estrogen protection hypothesis to schizophrenia spectrum outcomes requires further study. This dissertation also suggests that the psychosocial development hypothesis, which is not well-studied, may provide a promising new perspective on whether and why women appear to have better outcomes. This research also expands our knowledge of gender differences in schizophrenia spectrum disorders in China and highlights the importance of further research in other low- to middle-income countries. While the estrogen protection and psychosocial development hypotheses are surely important in our understanding of women with schizophrenia spectrum disorders, conducting this study using a dataset from China called attention to other social, political, and economic issues that women face that affect all aspects of their illness. These issues and their impact on women are likely different in high-income countries. Ultimately, the estrogen protection and psychosocial development hypotheses can only be understood within the complex context of women’s lived experience with schizophrenia spectrum disorders.

Environmental and genetic factors contribute to the development of schizophrenia. For example, epidemiological evidence has linked infections during pregnancy with increased incidence of schizophrenia in the adult offspring. At the same time mutation to DISC1, a protein involved in neurone migration and synaptic plasticity, is an important genetic risk for the disorder. Accordingly, the aim of this project was to determine if these environmental and genetic influences converge along a common pathogenic pathway leading to schizophrenia. Using a model of prenatal infection by bacterial endotoxin in rodents, we demonstrated a 50% reduction in DISC1 protein expression in the hippocampus and cortex of juvenile offspring. In addition, we found a significant induction of prostaglandins (final mediators of the inflammatory process) in the fetal brain while many cytokines remained unaltered. Taken together our results identify prostaglandins as potential mediators of the teratogenic effects of prenatal infection and show that prenatal infection itself can affect systems related to genetic risk factors for schizophrenia, in this case DISC1.

No description available.

Um aumento da atividade da PLA2 e alterações do sistema dopaminérgico tem sido descrito em esquizofrenia. No presente estudo, foram investigados os efeitos da atividade da PLA2 sobre os receptores D1 e D2 em cérebro post mortem de 10 sujeitos. Foi encontrado que a PLA2GVI é responsável por 85% do total de atividade da PLA2 no cérebro. A estimulação da PLA2GVI (por EDTA) aumentou a afinidade de D1 em estriado e em CPF e diminuiu a afinidade de D2 em estriado. A inibição da PLA2GVI (por BEL) diminuiu a afinidade de D1 em estriado, e em CPF e CT. A estimulação da PLA2GVI resultou em aumento na densidade de D1 em CPF e CT, e de D2 em estriado. Uma elevação da PLA2 em esquizofrenia poderia contribuir para a biologia da doença através de alterações na neurotransmissão dopaminérgica / Increased PLA2 activity and dopaminergic alterations have been described in schizophrenia. In the present study it was investigated the effects of PLA2 activity on D1 and D2 receptors in post mortem brain of 10 subjects. It was found that PLA2GVI corresponds to 85% of all PLA2 activity in the brain. The stimulation of PLA2GVI (by EDTA) increased D1 affinity in striatum and in PFC, and decreased D2 affinity in striatum. Conversely, the inhibition of PLA2GVI (using BEL) decreased D1 affinity in striatum, PFC and TC. The stimulation of PLA2GVI increased D1 density in PFC and TC, as well as the D2 density in striatum. The increased PLA2 activity in schizophrenia may contribute to the biology of the disease through alterations in dopaminergic neurotransmission