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Current title of PhD project: "Developing novel mouse models of neuropsychiatric
diseases based on the second hit hypothesis: Combination of genetic and environmental risk factors"
My work will start out with two genetic mouse models relevant for neuropsychiatric diseases:
(1) A model targeting the MECP2 gene. MECP2 (X-linked methyl-CpG-binding protein2) acts as a
transcriptional repressor. MECP2 loss-of-function causes Rett syndrome, an autism spectrum disorder
affecting mainly females. MECP2 overexpression (100%) also leads to a disorder characterized by autistic
features and mental retardation. Since both extremes result in similar phenotypes, I am planning to
investigate MECP2 mildly overexpressing (40%) mice. These mice will undergo comprehensive behavioural
screening and, dependent on the phenotype, be challenged with a second hit, e.g. social isolation.
(2) ST8Sia-II knockout mice (NCAM polysialylation defect) will be investigated in connection with chronic
cannabis (THC) exposure during puberty (=second hit). ST8Sia-II (sialyltransferase II) is one of
mainly two enzymes responsible for biosynthesis of polysialic acid (PSA) on NCAM (neural cell adhesion
molecule), and thus involved in regulating NCAM function during synaptic re-arrangement and re-organization.
ST8Sia-II involvement in PSA-NCAM interaction may underlie its role in schizophrenia, believed to be a disorder
of neural connectivity. Lack of ST8Sia-II leads to disturbed connectivity which is partly compensated by other
PSA species. We hypothesize that this compensation will be severely disturbed by cannabis, known to affect PSA-NCAM.
In fact, human studies have shown that cannabis abuse during adolescence leads to an earlier onset of schizophrenia.
It is my aim to investigate both early and late effects of chronic cannabis exposure in ST8Sia-II null mutant mice
as a dual hit model for the development of a schizophrenic phenotype.
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