Forsøksdyr: Impact of DNA glycosylases on the neuronal epigenome underlying memory formation

Godkjenningsdato 12.05.2020

Godkjenningsperiode 01.06.2020-01.06.2022

Accumulation of DNA damage is one of the causative factors of ageing and increases the risk of a wide range of neurodegenerative diseases. Ogg1 and Mutyh DNA glycosylases initiate base excision repair and conventionally cooperate to prevent mutations associated with oxidative DNA damage. In mice loss of Ogg1 and Mutyh alters memory formation in the Morris water maze paradigm and leads to changes in the hippocampal transcriptome independent of DNA damage accumulation.
Emerging evidence suggests a non-canonical function of DNA glycosylases in regulating gene expression by acting as potential readers of epigenetic modifications. However, the impact of DNA glycosylases on the epigenetic landscape underlying higher cognitive functions remains unknown.
Therefore, we would like to use wild type (WT), Ogg1-/-, Mutyh-/- and Ogg1-/- Mutyh-/- mice to further study the role of impaired oxidative base lesion repair in memory formation and to discover novel molecular targets for future therapeutic approaches. In this application we would like to introduce a behavioral task in order to more rigorously test for changes in memory function and to investigate the underlying molecular mechanisms of Ogg1 and Mutyh on the neuronal epigenome. We would like to subject mice to a commonly and widely used behavioral paradigm known as contextual fear conditioning. This test will give us the possibility to unravel the Ogg1- and Mutyh-dependent epigenetic network underlying both short- and long-term memory formation. Contextual fear conditioning tests higher associative learning as opposed to spontaneous exploration of novelty in the novel object recognition test. No severe phenotype has been observed in breeding of our mouse models and this application is for behavior testing only and thus no adverse effects are expected. All our experiments are well planned to reduce the use of animals and for this project we would like to apply for 936 animals.