Dokument: Modeling DISC1-dependent chronic mental illnesses in vivo and in vitro: generation of a novel DISC1 transgenic rat

Titel:	Modeling DISC1-dependent chronic mental illnesses in vivo and in vitro: generation of a novel DISC1 transgenic rat
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=37418
URN (NBN):	urn:nbn:de:hbz:061-20160309-091734-0
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Troßbach, Svenja [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 29,43 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 09.03.2016 / geändert 09.03.2016
Beitragende:	Prof. Dr. med. Korth, Carsten [Betreuer/Doktorvater] Prof. Dr. Willbold, Dieter [Gutachter] Prof. Dr. Roßner, Moritz [Gutachter]
Stichwörter:	DISC1, transgenic rat, tgDISC1 rat, schizophrenia, dopamine, protein aggregation, biomarker
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibung:	Chronic mental illnesses (CMIs) such as schizophrenia, bipolar disorder, or recurrent major depression are long-lasting brain disorders, which show considerable phenotypical heterogeneity, even within a single clinical diagnosis. To date, the biological origins of CMIs remain elusive. Up to the present day, the diagnosis of mental illness patients relies exclusively on a clinical interview and self-reporting of symptoms and is in the absence of distinct biological diagnostic markers often based on exclusion of other disorders. It is conceivable that the existing clinical diagnostic boundaries might not mirror a suspected biology. One possible method to define a subset of mental illness patients would be to detect the presence of aggregated proteins in the brain that accumulate during the course of CMIs as a result of disturbed proteostasis. Similar to established proteinopathies like the tauopathies or synucleinopathies, Disrupted-in-Schizophrenia 1 (DISC1) protein aggregates have been demonstrated to exist in a subset of post mortem brains from CMI patients, termed “DISC1opathies” for DISC1-dependent brain disorders. DISC1 is the protein product of a key candidate gene for CMI, which was first discovered in a Scottish pedigree with a familial mutation in the DISC1 gene and a high occurrence of various different clinical phenotypes. In this cumulative thesis, the interactions between neurotransmitter systems, cognitive impairments, and the disease-associated DISC1 protein were investigated in vivo, focused on, but not limited to, three major publications. In the first study, the role of DISC1 and its multimeric assembly states in the pathophysiology of CMI was investigated. In order to study the biological consequences of dysfunctional DISC1 assembly in vivo, the first transgenic rat model of a major mental illness gene was generated, the tgDISC1 rat modestly overexpressing the full-length non-mutant human DISC1 protein. Face validity of the tgDISC1 rat for DISC1opathies was established by comparable protein pathology in terms of DISC1 aggregates and behavioral phenotypes consistent with alterations in dopamine neurotransmission such as amphetamine supersensitivity, hyperexploratory behavior, and rotarod deficits. These findings were corroborated by alterations in the dopamine system of the striatum such as a proportionate increase in high affinity dopamine D2High receptors, elevated dopamine transporter levels, increased clearance of synaptic dopamine, and decreased total dopamine content. These findings suggest a bidirectional link between DISC1 assembly and dopamine homeostasis and highlight a functional role of DISC1 assemblies in CMI pathophysiology and in causing human DISC1opathies. In the second study, the value of lymphocytic DISC1 levels as a trait marker for the mental illness schizophrenia was investigated, and, as a major result, reduced DISC1 protein levels in lymphocytes of patients with schizophrenia were discovered. Since the study was also designed to investigate the influence of smoking, a prominent co-morbidity of schizophrenia, it was discovered that smoking itself reduced lymphocytic DISC1 protein significantly, although not to the extent of overriding the trait level. Finally, to investigate whether nicotine treatment could alter DISC1 assembly status, decreased levels of aggregated DISC1 species in the mPFC of rats sub-chronically treated with nicotine were detected, also indicating an influence of the cholinergic system in DISC1 aggregation. In the third study, the influence of intranasal application of dopamine (IN-DA) on age-dependent memory decline in aged rats was investigated. In a spatial object recognition paradigm the memory deficit of aged rats could be rescued by IN-DA treatment inducing increased specific exploration of the novel object. The presented studies advanced the understanding of the role of DISC1 in chronic mental illness, suggesting a physiological function of DISC1 aggregates in the brain that regulates dopamine homeostasis.
Rechtliche Vermerke:	Licences for reproduction of the full articles for use in this dissertation in print and electronic format were obtained by the author : 1) Licence number: 3821241413907, Elsevier 2) Licence number: 3821241224876, Elsevier
Lizenz:	Urheberrechtsschutz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie
Dokument erstellt am:	09.03.2016
Dateien geändert am:	09.03.2016
Promotionsantrag am:	04.05.2015
Datum der Promotion:	15.09.2015