RT Journal Article SR Electronic T1 Tet2 negatively regulates memory fidelity JF bioRxiv FD Cold Spring Harbor Laboratory SP 843581 DO 10.1101/843581 A1 Kristine E. Zengeler A1 Caroline P. Gettens A1 Hannah C. Smith A1 Mallory M. Caron A1 Xinyuan Zhang A1 Alexandra H. Howard A1 Andrea R. Boitnott A1 Alex R. Gogliettino A1 Anas Reda A1 Beth G. Malachowsky A1 Chun Zhong A1 Hongjun Song A1 Garrett A. Kaas A1 Andrew J. Kennedy YR 2019 UL http://biorxiv.org/content/early/2019/11/25/843581.abstract AB Despite being fully differentiated, DNA methylation is dynamically regulated in post-mitotic glutamatergic neurons in the CA1 of the hippocampus through competing active DNA methylation and de-methylation, a process that regulates neuronal plasticity. Active DNA methylation after learning is necessary for long-term memory formation, and active DNA de-methylation by the TET enzymes has been implicated as a counter-regulator of that biochemical process. We demonstrate that Tet2 functions in the CA1 as a negative regulator of long-term memory, whereby its knockdown across the CA1 or haploinsufficiency in glutamatergic neurons enhances the fidelity of hippocampal-dependent spatial and associative memory. Loci of altered DNA methylation were then determined using whole genome bisulfite sequencing from glutamatergic Tet2 haploinsufficient CA1 tissue, which revealed hypermethylation in the promoters of genes known to be transcriptionally regulated after experiential learning. This study demonstrates a link between Tet2 activity at genes important for memory formation in CA1 glutamatergic neurons and memory fidelity.