Loss of neuronal Tet2 enhances hippocampal-dependent cognitive function. Loss of neuronal Tet2 enhances hippocampal-dependent cognitive function

DNA methylation has emerged as a critical modulator of neuronal plasticity and cognitive function. Notwithstanding, the role of enzymes that demethylate DNA remain to be fully explored. Here, we report that loss of ten-eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), in adult neurons enhances cognitive function. In the adult mouse hippocampus, we detected an enrichment of Tet2 in neurons. Viral-mediated neuronal overexpression and RNA interference of Tet2 altered dendritic complexity and synaptic-plasticity-related gene expression in vitro. Overexpression of neuronal Tet2 in adult hippocampus, and loss of Tet2 in adult glutamatergic neurons, resulted in differential hydroxymethylation associated with genes involved in synaptic transmission. Functionally, overexpression of neuronal Tet2 impaired hippocampal-dependent memory, while loss of neuronal Tet2 enhanced memory. Ultimately, these data identify neuronal Tet2 as a molecular target to boost cognitive function. Overall design: RNA sequencing of hippocampal neuronal nuclei isolated from CamKIIaCreERT2;Tet2fl/fl mice vs WT Tet2fl/fl. RNA sequencing of E17 primary neuron cultures infected with lentivirus against luciferase or Tet2 (Samples 8-19).

DNA甲基化已被确立为神经元可塑性与认知功能的关键调控因子。尽管已有相关研究，介导DNA去甲基化的酶类其完整生物学功能仍有待全面探索。本研究报道，在成年神经元中敲除10-11易位甲基胞嘧啶双加氧酶2（ten-eleven translocation methylcytosine dioxygenase 2, Tet2）——该酶可催化5-甲基胞嘧啶（5-methylcytosine, 5mC）氧化为5-羟甲基胞嘧啶（5-hydroxymethylcytosine, 5hmC）——可显著增强认知功能。我们在成年小鼠海马体的神经元中检测到Tet2的富集表达。通过病毒介导的神经元过表达与RNA干扰技术，体外实验证实Tet2可调控树突复杂度与突触可塑性相关基因的表达。在成年海马神经元中过表达Tet2，或是在成年谷氨酸能神经元中敲除Tet2，均可引发与突触传递功能相关基因的差异性羟甲基化修饰。功能实验结果显示，神经元过表达Tet2会损伤海马依赖型记忆，而敲除神经元Tet2则可增强记忆能力。综上，本研究明确神经元Tet2可作为提升认知功能的分子靶点。整体实验设计：对CamKIIαCreERT2;Tet2fl/fl小鼠与野生型Tet2fl/fl小鼠分离得到的海马神经元细胞核进行RNA测序；对感染靶向荧光素酶或Tet2的慢病毒的E17原代神经元培养物进行RNA测序（样本8-19）。