Epigenomic Imaging of Neuropsychiatric Diseases

Epigenomic Imaging of Neuropsychiatric Diseases

The Role of Chromatin Plasticity in Schizophrenia and Anxiety Diseases

Sanaz Bahari Javan

Doctoral thesis

Date of Examination: 2013-01-29

Date of issue: 2013-12-13

Advisor: Fischer, André Prof. Dr.

Referee: Fischer, André Prof. Dr.

Referee: Hörner, Michael Prof. Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0022-6093-A

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Abstract

English

Schizophrenia is a severe neuropsychiatric disorder with high phenotypic complexity and multifactorial inheritance. Cognitive dysfunctions have been identified as the core feature of the disease and they are resistant to treatment with available antipsychotics. Impaired working memory and disrupted sensorimotor gating are the cognitive hallmarks of schizophrenia. Both of these cognitive dysfunctions are defined as cognitive endophenotypes that present a biomarker and guidepost for identification of the cause and course of schizophrenia. The etiopathogenesis of schizophrenia is thought to rely on genome and environment (GxE) interactions. Epigenetic enzymes such as histone-deacetylases (HDACs) are key mediators of GxE interactions. HDACs remove acetyl-groups of histone-proteins in response to environment stimuli, thereby changing the chromatin structure resulting into differential gene-expression important for cognition. Deregulated histone-acetylation leads to impairments in learning and memory. Two independent human post-mortem studies have reported elevated HDAC1 levels in the hippocampus and prefrontal cortex of individuals with schizophrenia, with both brain regions being important for the regulation of cognitive endophenotypes of schizophrenia. My results showed, that overexpression of neuronal HDAC1 in the prefrontal cortex of adult mice resulted in schizophrenia-like symptoms such as increased anxiety, depressive-like behavior, impaired fear extinction and cognitive endophenotypes such as impaired working memory performance and deficits in sensorimotor gating function. Inhibition of HDAC1 ameliorated such phenotypes. Moreover, environmental risk factors for schizophrenia such as early life stress induced cognitive endophenotypes of schizophrenia and mediated the up-regulation of prefrontal cortical HDAC1, simulating the situation observed in the post-mortem prefrontal cortex tissue of individuals with schizophrenia. . Interestingly, while manipulating neuronal HDAC1 levels in the prefrontal cortex of mice caused schizophrenia-like phenotypes, affecting neuronal HDAC1 levels in the dorsal hippocampus had no impact on such behaviors. Instead under physiological conditions, HDAC1 in the dorsal hippocampus regulates the extinction of fear memories in mice by transcriptional repression of Immediate Early Genes (IEG´s). In conclusion, these data indicate a brain-region specific function of HDAC1 in cognition and emotional behavior and provide important knowledge on the role of HDAC1 in the adult brain.

Keywords: Epigenetic mechanism; GenomexEnvironment interactions; Schizophrenia; Fear Extinction; Cognitive Endophenotypes