Section on Synapse Development Plasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States.
Advanced Imaging Core, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, United States.
Mol Psychiatry. 2021 Sep;26(9):4633-4651. doi: 10.1038/s41380-021-01038-9. Epub 2021 Feb 15.
Mitochondria are cellular ATP generators. They are dynamic structures undergoing fission and fusion. While much is known about the mitochondrial fission machinery, the mechanism of initiating fission and the significance of fission to neurophysiology are largely unclear. Gamma oscillations are synchronized neural activities that impose a great energy challenge to synapses. The cellular mechanism of fueling gamma oscillations has yet to be defined. Here, we show that dysbindin-1, a protein decreased in the brain of individuals with schizophrenia, is required for neural activity-induced fission by promoting Drp1 oligomerization. This process is engaged by gamma-frequency activities and in turn, supports gamma oscillations. Gamma oscillations and novel object recognition are impaired in dysbindin-1 null mice. These defects can be ameliorated by increasing mitochondrial fission. These findings identify a molecular mechanism for activity-induced mitochondrial fission, a role of mitochondrial fission in gamma oscillations, and mitochondrial fission as a potential target for improving cognitive functions.
线粒体是细胞的 ATP 生成器。它们是经历裂变和融合的动态结构。虽然人们对线粒体裂变机制了解很多，但裂变的启动机制以及裂变对神经生理学的意义在很大程度上还不清楚。γ 振荡是同步的神经活动，对突触施加巨大的能量挑战。为 γ 振荡提供燃料的细胞机制尚未确定。在这里，我们表明，精神分裂症患者大脑中减少的蛋白 dysbindin-1 通过促进 Drp1 寡聚化来促进神经活动诱导的裂变，从而需要分裂。这个过程被 γ 频率活动所参与，反过来又支持 γ 振荡。dysbindin-1 缺失小鼠的 γ 振荡和新物体识别受损。通过增加线粒体裂变可以改善这些缺陷。这些发现确定了活性诱导的线粒体裂变的分子机制、线粒体裂变在 γ 振荡中的作用以及线粒体裂变作为改善认知功能的潜在靶点。
