Hermes Gretchen, Nagy David, Waterson Michael, Zsarnovszky Attila, Varela Luis, Hajos Mihaly, Horvath Tamas L
Yale School of Medicine, Department of Psychiatry, 300 George St., Suite 901, New Haven, CT 06511, USA.
Yale School of Medicine, Section of Comparative Medicine, 310 Cedar St., BML 330, P.O. Box 208016, New Haven, CT 06520-8016, USA.
Mol Metab. 2016 Apr 9;5(6):415-421. doi: 10.1016/j.molmet.2016.04.002. eCollection 2016 Jun.
BACKGROUND/PURPOSE: Major psychiatric illnesses, affecting 36% of the world's population, are profound disorders of thought, mood and behavior associated with underlying impairments in synaptic plasticity and cellular resilience. Mitochondria support energy demanding processes like neural transmission and synaptogenesis and are thus points of broadening interest in the energetics underlying the neurobiology of mental illness. These experiments interrogated the importance of mitochondrial flexibility in behavior, synaptic and cortical activity in a mouse model.
We studied mice with ablated uncoupling protein-2 expression (UCP2 KO) and analyzed cellular, circuit and behavioral attributes of higher brain regions.
We found that mitochondrial impairment induced by UCP2 ablation produces an anxiety prone, cognitively impaired behavioral phenotype. Further, NMDA receptor blockade in the UCP2 KO mouse model resulted in changes in synaptic plasticity, brain oscillatory and sensory gating activities.
We conclude that disruptions in mitochondrial function may play a critical role in pathophysiology of mental illness. Specifically, we have shown that NMDA driven behavioral, synaptic, and brain oscillatory functions are impaired in UCP2 knockout mice.
背景/目的：主要精神疾病影响着全球36%的人口，是与突触可塑性和细胞恢复力潜在损伤相关的严重思维、情绪和行为障碍。线粒体支持诸如神经传递和突触形成等能量需求过程，因此成为人们对精神疾病神经生物学背后能量学兴趣不断扩大的关注点。这些实验探究了线粒体灵活性在小鼠模型行为、突触和皮层活动中的重要性。
我们研究了敲除解偶联蛋白2表达的小鼠（UCP2基因敲除小鼠），并分析了高等脑区的细胞、神经回路和行为特征。
我们发现，UCP2基因敲除引起的线粒体损伤产生了易焦虑、认知受损的行为表型。此外，UCP2基因敲除小鼠模型中的NMDA受体阻断导致突触可塑性、脑振荡和感觉门控活动发生变化。
我们得出结论，线粒体功能破坏可能在精神疾病的病理生理学中起关键作用。具体而言，我们已经表明，在UCP2基因敲除小鼠中，NMDA驱动的行为、突触和脑振荡功能受损。
