Data from: 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 premanifest Huntington’s disease pathogenesis long before the onset of clinical symptoms.

捕捉亨廷顿病（Huntington’s disease）极早期发病阶段（very far from disease onset，以下简称VFDO）的核心功能变化，或是成功开发治疗手段的关键。本研究聚焦VFDO阶段，对临床前Hdh150敲入小鼠的神经元微环路进行了评估。通过活体双光子钙离子成像技术，我们在视觉皮层（visual cortex）——临床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，其特征为神经元活动增强、同步性提升以及神经元过度激活。该异常环路同时伴随小鼠行为学异常。此外，本研究证实抗糖尿病药物二甲双胍（metformin）可降低异常亨廷顿蛋白负荷，并完全恢复早期神经网络活动模式与行为学异常。这种以神经网络为核心的研究方法，揭示了临床症状出现前极早阶段的关键易感窗口，并证实二甲双胍有望成为在临床症状发作前尽早启动的、针对临床前亨廷顿病发病机制的慢性治疗候选药物。