Vetsuisse Faculty, University of Zurich 2016 Hannah Hamburg Institute of Veterinary Pathology ivpz@vetpath.uzh.ch Simultaneous effects on interneuron and dopaminergic system development in a transgenic rat model for sporadic schizophrenia Despite continuous effort, unequivocal neuroanatomical features for sporadic or familial schizophrenia could not yet be defined. A standardized characterization might give rise to issues because of the discrete nature of changes, the heterogeneity of

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... causes, and a high intersubject variability. Disrupted-in-schizophrenia 1 (DISC1) is a risk gene for chronic mental illnesses and its overexpression is a vulnerability factor for a subset of sporadic disease types. In this study we report on neuroanatomical abnormalities in transgenic rats overexpressing human full-length, non-mutant DISC1, modelling a subset of sporadic chronic mental illness. A decreased density of dopaminergic neurons in the substantia nigra and reduced dopaminergic fibres in the striatum, but not the amygdala, were detected in tgDISC1 rats. Parvalbumin-interneuron distribution was shifted to the deeper cortical layers and calbindin-interneurons showed a subtle decrease in their total number. In vivo MRI and voxel-wise tensor based morphometry revealed a slight volumetric decrease of the corpus callosum which could be confirmed microscopically. In this study, we demonstrate that tgDISC1 rats display concurrent neuroanatomical abnormalities in two important neuronal systems. Our analysis gives an insight into neuroanatomical changes of the tgDISC1 rat model that may contribute to a clearer definition of neuroanatomical abnormalities associated with subsets of human sporadic schizophrenia. Key words: Disrupted-in-Schizophrenia 1 (DISC1); dopaminergic system; interneurons; neuroanatomy; schizophrenia Vetsuisse-Fakultät Universität Zürich 2016 Hannah Hamburg Institut für Veterinärpathologie ivpz@vetpath.uzh.ch Eine einheitliche neuroanatomische Charakterisierung sporadischer sowie erblicher Schizophrenieformen konnte bislang trotz stetiger Bemühungen nicht definiert werden. Sie erweist sich als schwierig aufgrund der Feinheit der Veränderungen, der Heterogenität biologischer Ursachen und der hohen interindividuellen Variabilität. Disrupted-in-Schizophrenia 1 (DISC1) ist ein Risikogen für chronisch-mentale Erkrankungen, seine Überexpression prädestiniert für eine Subgruppe sporadischer Erkrankungsformen. In dieser Studie beschreiben wir neuroanatomische Veränderungen eines transgenen Rattenmodells mit Überexpression von nicht-mutiertem, humanem DISC1 in voller Länge. In tgDISC1 Ratten wurden eine verringerte Dichte dopaminerger Neuronen in der Substantia nigra und eine reduzierte dopaminerge Faserdichte im Striatum, jedoch nicht der Amygdala gefunden. Die Verteilung der Parvalbumin-Interneuronen war in die tiefen Kortexschichten verschoben und Calbindin-Interneuronen zeigten eine dezent verringerte Gesamtanzahl. Im in vivo MRT und in Voxel-basierter Morphometrie fiel eine geringe Volumenminderung des Corpus callosum auf, was auch histologisch bestätigt werden konnte. Diese Studie zeigt, dass tgDISC1 Ratten gleichzeitig in zwei wichtigen neuronalen Schaltkreisen Abweichungen aufweisen. Sie gibt einen Einblick in neuroanatomische Veränderungen dieses Models und kann zu einer klareren Definition histologischer Abweichungen in Subgruppen sporadischer Schizophrenie des Menschen beitragen. Stichwörter: Disrupted-in-schizophrenia 1 (DISC1); dopaminerges System; Interneuronen; Neuroanatomie; Schizophrenie Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-131122 Dissertation Published Version Originally published at: Hamburg, Hannah. Simultaneous effects on interneuron and dopaminergic system development in a transgenic rat model for sporadic schizophrenia. 2016, Schizophrenia 1 (DISC1) , and for which aberrant dopamine homeostasis consistent with some schizophrenia phenotypes has previously been reported. Neuroanatomical analysis revealed a reduced density of dopaminergic neurons in the substantia nigra and reduced dopaminergic fibres in the striatum. Parvalbumin-positive interneuron occurrence in the somatosensory cortex was shifted from layers II/III to V/VI, and the number of calbindin-positive interneurons was slightly decreased. Reduced corpus callosum thickness confirmed trend-level observations from in vivo MRI and voxel-wise tensor based morphometry. These neuroanatomical changes help explain functional phenotypes of this animal model, some of which resemble changes observed in human schizophrenia post mortem brain tissues. Our findings also demonstrate how a single molecular factor, DISC1 overexpression or misassembly, can account for a variety of seemingly unrelated morphological phenotypes and thus provides a possible unifying explanation for similar findings observed in sporadic schizophrenia patients. Our anatomical investigation of a defined model for sporadic mental illness enables a clearer definition of neuroanatomical changes associated with subsets of human sporadic schizophrenia. To date, unequivocal neuroanatomical features have been demonstrated neither for sporadic nor for familial schizophrenia. Here, we investigated the neuroanatomical changes in a transgenic rat model for a subset of sporadic chronic mental illness (CMI), which modestly overexpresses human full-length, nonmutant Disrupted-in- To date, neuropathological features correlating to the exclusive clinical diagnosis "schizophrenia" are controversial, likely due to 1) the subtlety of changes, 2) the heterogeneity of underlying biological causes, and 3) the high inter-subject variability of brain microanatomy in human individuals. Efforts to characterize morphological changes have been made since the clinical description of the condition utilizing both in vivo imaging as well as post mortem approaches. Even though the clinical success of dopamine antagonists in treating the acute psychotic phase of schizophrenia in a majority of patients has led to the biological "dopamine hypothesis" of schizophrenia (reviewed in ref. 1) and thus helped to define a common ground for this clinical syndrome, neuropathological investigations