Tet1 Is Critical for Neuronal Activity-Regulated Gene Expression and Memory Extinction

• Published in: Neuron (Cambridge, Mass.) Vol. 79; no. 6; pp. 1109 - 1122
• Main Authors: Rudenko, Andrii, Dawlaty, Meelad M., Seo, Jinsoo, Cheng, Albert W., Meng, Jia, Le, Thuc, Faull, Kym F., Jaenisch, Rudolf, Tsai, Li-Huei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.09.2013; Elsevier Limited
• Subjects: Age Factors; Analysis of Variance; Animal cognition; Animals; Anxiety - genetics; Anxiety - physiopathology; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Brain; Cerebral Cortex - cytology; Cloning; Conditioning, Classical - physiology; Deoxyribonucleic acid; Depression - genetics; Depression - metabolism; Disease Models, Animal; DNA; DNA methylation; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - physiology; Enzymes; Exploratory Behavior - physiology; Extinction, Psychological - physiology; Gene expression; Gene Expression Profiling; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Genomes; Grants; Hippocampus - cytology; In Vitro Techniques; Locomotion - genetics; Long-Term Synaptic Depression - genetics; Male; Maze Learning; Memory; Methoxyhydroxyphenylglycol - analogs & derivatives; Methoxyhydroxyphenylglycol - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins - metabolism; Neurons - physiology; Neurosciences; Oligonucleotide Array Sequence Analysis; Proteins; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-fos - metabolism; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Rodents; Software; Stem cells; Synapses - genetics; Synapsins - metabolism
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2013.08.003

The ten-eleven translocation (Tet) family of methylcytosine dioxygenases catalyze oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and promote DNA demethylation. Despite the abundance of 5hmC and Tet proteins in the brain, little is known about the functions of the neuronal Tet enzymes. Here, we analyzed Tet1 knockout mice (Tet1KO) and found downregulation of multiple neuronal activity-regulated genes, including Npas4, c-Fos, and Arc. Furthermore, Tet1KO animals exhibited abnormal hippocampal long-term depression and impaired memory extinction. Analysis of the key regulatory gene, Npas4, indicated that its promoter region, containing multiple CpG dinucleotides, is hypermethylated in both naive Tet1KO mice and after extinction training. Such hypermethylation may account for the diminished expression of Npas4 itself and its downstream targets, impairing transcriptional programs underlying cognitive processes. In summary, we show that neuronal Tet1 regulates normal DNA methylation levels, expression of activity-regulated genes, synaptic plasticity, and memory extinction. •Tet1KO mice display memory extinction impairment•Tet1KO mice exhibit abnormally enhanced hippocampal LTD•Npas4, c-Fos, Arc are downregulated in Tet1KO cortex and hippocampus•Npas4 promoter is hypermethylated in Tet1KO cortex and hippocampus Rudenko et al. report that Tet1 loss impairs hippocampal LTD and memory extinction. They find downregulation of activity-regulated genes in Tet1KO mice and hypermethylation of Npas4 promoter in naive Tet1KO mice and after memory extinction. Thus, Tet1 regulates activity-regulated genes and memory extinction.