C01

Role of Dnmt3a2 in the establishment and stability of experience-dependent cell ensembles

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In this project, we study the role of epigenetic mechanisms in long-term memory formation.

The hippocampus is thought to play a critical role in the formation and consolidation of new spatial memories via the establishment and stabilisation of new cell ensembles (also called assemblies). The
molecular pathways that regulate this process are still largely unknown.

A rapidly increasing body of evidence points to a crucial role of epigenetic mechanisms in regulating the consolidation of new spatial memories. In the current project we will investigate the role of a DNA methyltransferase (Dnmt3a2), an enzyme that catalyzes the transfer of a methyl group to cytosine, in spatial memory. The main working hypothesis is that Dnmt3a2 plays a critical role in the stabilization of new cell ensembles representing newly formed spatial memory. We propose that Dnmt3a2 regulates the expression of plasticity-related genes that induce the plastic changes believed to underlie the altered connectivity in activated neurons. Our hypothesis will be tested by bi-directionally manipulating the expression levels of Dnmt3a2 in the mouse hippocampus and monitoring the formation of new cell ensembles as mice explore novel environments. In a second series of experiments, we will investigate how exposure to novel spatial environments affects the expression of Dnmt3a2 and whether experience-driven expression of Dnmt3a2 is modulated by sleep. Thereby, we will explore the functional role for Dnmt3a2 within neuronal ensembles that encode environment information. Finally, we will explore which down-stream genes change their expression following experimental manipulation of Dnmt3a2 level. This research project will provide new insight into how epigenetic mechanisms contribute to the formation and consolidation of new spatial memories.
Publications
Buetfering T, Allen K, Monyer H* Parvalbumin interneurons provide grid cell-driven recurrent inhibition in the medial entorhinal cortex. Nature Neurosci (in press)

Allen K, Rawlins NP, Bannerman DM, Csicsvari J. (2012) Hippocampal place cells can encode multiple trial-dependent features through rate remapping. J Neurosci 32: 14752-14766.

Oliveira AMM, Hemstedt TJ, Bading H* (2012) Rescue of aging-associated decline in Dnmt3a2 restores cognitive abilities. Nature Neurosci 15: 1111-1113.

Allen K, Fuchs EC, Jaschonek H, Bannerman DM, Monyer H* (2011) Gap junctions between interneurons are required for normal spatial coding in the hippocampus and short-term spatial memory. J Neurosci 31:6542-6552.

Oliveira AMM, Estevez MA, Hawk JD, Grimes S, Brindle PK, Abel T (2011) Subregion-specif- ic p300 conditional knock-out mice exhibit long-term memory impairments. Learn Mem 18:161-169.

Oliveira AMM, Hawk JD, Abel T and Havekes R (2010) Post-training reversible inactivation of the hippocampus enhances novel object recognition memory. Learn Mem 17:155-160.

Huxter J, Senior T, Allen K, O’Neill J, Csicsvari J (2008) Theta phase-specific codes for two-di- mensional position, trajectory, and heading in the hippocampus. Nature Neurosci 11:587- 594.

O’Neill J, Huxter J, Senior T, Allen K, Csicsvari J (2008) Reactivation of experience-dependent cell assembly patterns in the hippocampus. Nature Neurosci 11:209-215.

Oliveira AMM, Wood MA, McDonough C, Abel T (2007) Transgenic mice expressing a truncated form of p300 exhibit memory deficits. Learn Mem 14:564-572.

Wood MA, Attner M, Oliveira AMM, Brindle PK, Abel T. (2006) A transcription factor-binding do- main of the coactivator CBP is essential for long-term memory and the expression of specific target genes. Learn Mem 13:609-617.

*Principal investigators of other projects within the CRC