The balance of excitation and inhibition is essential for cortical information processing, relying on the tight orchestration of the underlying subcellular processes. Dynamic transcriptional control by DNA methylation, catalyzed by DNA methyltransferases (DNMTs), and DNA demethylation, achieved by ten–eleven translocation (TET)-dependent mechanisms, is proposed to regulate synaptic function in the adult brain with implications for learning and memory. However, focus so far is laid on excitatory neurons. Given the crucial role of inhibitory cortical interneurons in cortical information processing and in disease, deciphering the cellular and molecular mechanisms of GABAergic transmission is fundamental. The emerging relevance of DNMT and TET-mediated functions for synaptic regulation irrevocably raises the question for the targeted subcellular processes and mechanisms. In this study, we analyzed the role dynamic DNA methylation has in regulating cortical interneuron function. We found that DNMT1 and TET1/TET3 contrarily modulate clathrin-mediated endocytosis. Moreover, we provide evidence that DNMT1 influences synaptic vesicle replenishment and GABAergic transmission, presumably through the DNA methylation-dependent transcriptional control over endocytosis-related genes. The relevance of our findings is supported by human brain sample analysis, pointing to a potential implication of DNA methylation-dependent endocytosis regulation in the pathophysiology of temporal lobe epilepsy, a disease characterized by disturbed synaptic transmission.

中文翻译：

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DNA 甲基化介导的胞吞作用调节是小鼠抑制性皮质中间神经元突触功能调节的潜在机制。

兴奋和抑制的平衡对于皮层信息处理至关重要，依赖于基础亚细胞过程的紧密协调。通过 DNA 甲基化（由 DNA 甲基转移酶（DNMT）催化）和 DNA 去甲基化（由 10-11 易位（TET）依赖性机制实现）的动态转录控制被提议用于调节成人大脑中的突触功能，对学习和记忆产生影响。然而，到目前为止，重点放在兴奋性神经元上。鉴于抑制性皮层中间神经元在皮层信息处理和疾病中的关键作用，破译 GABA 能传递的细胞和分子机制至关重要。DNMT 和 TET 介导的突触调节功能的新兴相关性无可挽回地提出了靶向亚细胞过程和机制的问题。在这项研究中，我们分析了动态 DNA 甲基化在调节皮质中间神经元功能中的作用。我们发现 DNMT1 和 TET1/TET3 相反地调节网格蛋白介导的内吞作用。此外，我们提供了 DNMT1 影响突触囊泡补充和 GABA 能传递的证据，大概是通过对内吞相关基因的 DNA 甲基化依赖性转录控制。我们的研究结果的相关性得到了人脑样本分析的支持，指出了 DNA 甲基化依赖性内吞作用调节在颞叶癫痫的病理生理学中的潜在意义，颞叶癫痫是一种以突触传递紊乱为特征的疾病。