Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease

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 in vivo two-photon Ca2+ 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 anti-diabetic 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 preman...捕捉亨廷顿病（Huntington’s disease）早期、‘距离发病极早期（very far from disease onset，VFDO）’阶段的原始功能变化，或是成功治疗该病的关键所在。本研究聚焦VFDO阶段，对症状前Hdh150敲入小鼠的神经元微环路进行了评估。借助活体双光子钙离子（Ca²+）成像技术，我们在视觉皮层——症状前亨廷顿病最早受累的脑区之一——中发现了环路失调的早期模式：表现为活动水平升高、同步性增强以及神经元过度激活。上述异常同时伴随小鼠行为异常。此外我们证实，抗糖尿病药物二甲双胍可降低异常的亨廷顿蛋白负荷，并完全恢复早期的网络活动模式与行为异常。这种以网络为核心的研究方法，揭示了临床发病前极早阶段的脆弱关键窗口，并确立了二甲双胍作为一种可在症状前早期启动的慢性治疗候选药物的潜力。