Institute of Pathophysiology, Focus Program Translational Neurosciences, University Medical Center, Mainz, Germany.
Institute for Human Genetics, University Medical Center, Mainz, Germany.
Elife. 2018 Sep 4;7:e38744. doi: 10.7554/eLife.38744.
Catching primal functional changes in early, 'very far from disease onset' (VFDO) stages of Huntington's disease is likely to be the key to a successful therapy. Focusing on VFDO stages, we assessed neuronal microcircuits in premanifest Hdh150 knock-in mice. Employing two-photon Ca imaging, we revealed an early pattern of circuit dysregulation in the visual cortex - one of the first regions affected in premanifest Huntington's disease - characterized by an increase in activity, an enhanced synchronicity and hyperactive neurons. These findings are accompanied by aberrations in animal behavior. We furthermore show that the antidiabetic drug metformin diminishes aberrant Huntingtin protein load and fully restores both early network activity patterns and behavioral aberrations. This network-centered approach reveals a critical window of vulnerability far before clinical manifestation and establishes metformin as a promising candidate for a chronic therapy starting early in premanifest Huntington's disease pathogenesis long before the onset of clinical symptoms.
在亨廷顿病的早期、“远在疾病发病之前”（VFDO）阶段捕捉原始功能变化，很可能是成功治疗的关键。我们专注于 VFDO 阶段，评估了前显型 Hdh150 基因敲入小鼠的神经元微电路。通过双光子 Ca 成像，我们揭示了视觉皮层中电路失调的早期模式——这是前显型亨廷顿病最早受影响的区域之一——其特征是活性增加、同步性增强和神经元过度活跃。这些发现伴随着动物行为的异常。我们还表明，抗糖尿病药物二甲双胍可减少异常亨廷顿蛋白负荷，并完全恢复早期网络活动模式和行为异常。这种以网络为中心的方法揭示了在临床症状出现之前，远在疾病发病之前的一个关键脆弱窗口期，并将二甲双胍确立为一种有前途的候选药物，用于在临床症状出现之前，在亨廷顿病发病机制的前显期就开始进行慢性治疗。
