The influence of epigenetic alterations on synaptic function and memory

by Henning Schroeder
Doctoral thesis
Date of Examination:2021-10-15
Date of issue:2022-08-24
Advisor:Prof. Dr. André Fischer
Referee:Ph.D. Camin Dean
Referee:Prof. Dr. Tiago Fleming Outeiro
Referee:Prof. Dr. Ralf Heinrich
Referee:Dr. Jan Clemens
Referee:Prof. Dr. Thomas Dresbach
Persistent Address: http://dx.doi.org/10.53846/goediss-9417

 

 

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Abstract

English

While memory formation is traditionally linked to changes in synaptic structure, the transcriptional processes enabling these changes are often understudied. Even though novel protein synthesis is the basis of long-term memory formation, the exact interplay between synaptic stimulation and transcriptional regulation remain elusive. In a former study, the Fischer lab could show that changes in the epigenetic code, one of the regulators of transcription, can be directly linked to memory performance in mice. The manipulation of this code via the inhibition of proteins that actively change it by adding or removing chemical groups, or marks, to the chromatin, directly influences the transcriptional levels of neuronal genes. In this thesis I focus on a group of proteins that „read“ a chromatin marks shown to be relevant for the expression of memory related genes and which, if reinstated in old mice, is beneficial for certain aspects of their memory performance. The chromatin readers in question, BET (bromodomain extra-terminal domain-containing) chromatin readers named after their functional groups, play a prominent role in cancer, which led to the development of small molecule inhibitors targeting their binding pockets. Published experiments we performed using these inhibitors on mice in memory tasks revealed a beneficial effect, contrary to what we expected from former studies. BET inhibitors are however not specific to single members of the BET protein family. In this these we utilized cKO mouse lines and viral-induced overexpression of specific BETs in combination with next generation sequencing, bioinformatics, behavior, immunohistochemistry, live cell imaging and code-based analysis thereof, to link the influence of BETs on transcription in neurons and brains to behavioral as well as physiological phenotypes in order to assess their potential as drug targets for alleviation of memory-related symptoms in neurodegenerative diseases. We could show that BETs not only play an important role in the regulation of neuronal gene expression, development and function, but also that the pharmacological manipulation of their binding capabilities could have potentially detrimental effects on the organism as a whole and memory performance specifically.
Keywords: chromatin readers; BET; neurobiology; behavior; epigenetics; RNAseq; learning & memory; NGS; bioinformatics
 
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