Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America.
PLoS One. 2011;6(9):e25253. doi: 10.1371/journal.pone.0025253. Epub 2011 Sep 28.
Responding to errors is a critical first step in learning from mistakes, a process that is abnormal in schizophrenia. To gain insight into the neural and molecular mechanisms of error processing, we used functional MRI to examine effects of a genetic variant in methylenetetrahydrofolate reductase (MTHFR 677C>T, rs1801133) that increases risk for schizophrenia and that has been specifically associated with increased perseverative errors among patients. MTHFR is a key regulator of the intracellular one-carbon milieu, including DNA methylation, and each copy of the 677T allele reduces MTHFR activity by 35%.
METHODOLOGY/PRINCIPAL FINDINGS: Using an antisaccade paradigm, we found that the 677T allele induces a dose-dependent blunting of dorsal anterior cingulate cortex (dACC) activation in response to errors, a pattern that was identical in healthy individuals and patients with schizophrenia. Further, the normal relationship between dACC activation and error rate was disrupted among carriers of the 677T allele.
CONCLUSIONS/SIGNIFICANCE: These findings implicate an epigenetic mechanism in the neural response to errors, and provide insight into normal cognitive variation through a schizophrenia risk gene.
错误响应是从错误中学习的关键第一步，而这一过程在精神分裂症中是异常的。为了深入了解错误处理的神经和分子机制，我们使用功能磁共振成像技术研究了亚甲基四氢叶酸还原酶（MTHFR 677C>T，rs1801133）的遗传变异对其的影响，该变异会增加精神分裂症的风险，并且与患者中持续错误的增加有特定关联。MTHFR 是细胞内一碳代谢环境的关键调节因子，包括 DNA 甲基化，每个 677T 等位基因的出现会使 MTHFR 活性降低 35%。
方法/主要发现：使用反扫视范式，我们发现 677T 等位基因导致背侧前扣带皮层（dACC）对错误的激活呈剂量依赖性减弱，这种模式在健康个体和精神分裂症患者中是相同的。此外，677T 等位基因携带者的 dACC 激活与错误率之间的正常关系被打破。
结论/意义：这些发现表明，在错误的神经反应中存在一种表观遗传机制，并通过一个精神分裂症风险基因提供了对正常认知变异的深入了解。
