Epigenetik in der Schizophrenie und der Einfluss von Histon-Deacetylasen auf die Arbeitsgedächtnisfunktion

Epigenetics in schizophrenia and the influence of histone deacetylases on working memory

by Sebastian Löns
Doctoral thesis
Date of Examination:2015-10-13
Date of issue:2015-10-07
Advisor:Prof. Dr. André Fischer
Referee:Dr. Oliver Pd Wirths
Referee:Prof. Dr. Martin Oppermann
Persistent Address: http://dx.doi.org/10.53846/goediss-5296

 

 

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Abstract

English

Schizophrenia is a chronic disease leading to impairment in social and occupational functioning. The etiology remains elusive. Current concepts presume a genetic susceptibility, which in combination with environmental stimuli leads to the clinical manifestation. Cognitive dysfunction, especially deficits in working memory are regarded core deficits in schizophrenia. Working memory function is thought to be located in the prefrontal cortex. Epigenetics in a neuroscientific definition describes the mechanisms in which external stimuli change gene expression in postmitotic brain cells. The mechanisms of histone acetylation and DNA methylation are especially well characterized. It is known, that the formation of long-term memory involves epigenetic processes. The present thesis deals with the question, whether epigenetic mechanisms also regulate working memory processes. Postmortal brain samples from the dorsolateral PFC showed significant hyperacetylation at histone 4 in schizophrenics and overexpression of hdac1 while other nuclear HDAC were normally expressed. Determination of working memory-related receptors showed a reduction of muscarinic acetylcholine-receptor 1 (ChRM1) and of AMPA glutamate receptor, subunit 1 (GluR1) in schizophrenics. Investigation of epigenetic processes showed a hypomethylation of the chrm1-promotor region. To further determine the epigenetic influence on working memory processes in a prospective manner we examined the effect of the histone deacetylase inhibitors (HDACi) sodiumbutyrate and phenylbutyrate in a methionine-induced mouse model for schizophrenia. Chronic application of intraperitoneal methionine did not result in reduced working memory performance in the novel object recognition task. Furthermore chronic application of HDACi intraperitoneal did not enhance working memory performance in untreated mice in the Y-maze task. These results indicate a possible global epigenetic deregulation in the schizophrenic pathophysiology and an epigenetic regulation of working memory-relevant receptors. Nevertheless HDAC inhibition did not result in altered working memory function
Keywords: schizophrenia; epigenetics; working memory; histone acetylation
Schlagwörter: Schizophrenie; Epigenetik; Arbeitsgedächtnis; Histonacetylierung
 
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