Ikefuama Ebenezer C, Slaviero Ashley N, Schalau Raegan, Gott Madison, Tree Maya O, Dunbar Gary L, Rossignol Julien, Hochgeschwender Ute
Program in Neuroscience, Central Michigan University, Mount Pleasant, MI 48859, USA.
Biochemistry, Cell and Molecular Biology Program, Central Michigan University, Mount Pleasant, MI 48859, USA.
bioRxiv. 2024 Jul 24:2024.07.24.604946. doi: 10.1101/2024.07.24.604946.
Early stages of Huntington's disease (HD) before the onset of motor and cognitive symptoms are characterized by imbalanced excitatory and inhibitory output from the cortex to striatal and subcortical structures. The window before the onset of symptoms presents an opportunity to adjust the firing rate within microcircuits with the goal of restoring the impaired E/I balance, thereby preventing or slowing down disease progression. Here, we investigated the effect of presymptomatic cell-type specific manipulation of activity of pyramidal neurons and parvalbumin interneurons in the M1 motor cortex on disease progression in the R6/2 HD mouse model. Our results show that dampening excitation of Emx1 pyramidal neurons or increasing activity of parvalbumin interneurons once daily for 3 weeks during the pre-symptomatic phase alleviated HD-related motor coordination dysfunction. Cell-type-specific modulation to normalize the net output of the cortex is a potential therapeutic avenue for HD and other neurodegenerative disorders.
亨廷顿舞蹈病（HD）在运动和认知症状出现之前的早期阶段，其特征是从皮层到纹状体及皮层下结构的兴奋性和抑制性输出失衡。症状出现前的这段窗口期提供了一个机会，可以通过调整微回路内的 firing rate 来恢复受损的E/I平衡，从而预防或减缓疾病进展。在此，我们研究了在R6/2 HD小鼠模型中，对M1运动皮层锥体神经元和小白蛋白中间神经元进行症状前细胞类型特异性活动操纵对疾病进展的影响。我们的结果表明，在症状前期，每天对Emx1锥体神经元的兴奋性进行一次抑制，或对小白蛋白中间神经元的活动进行一次增强，持续3周，可缓解与HD相关的运动协调功能障碍。对皮层净输出进行细胞类型特异性调节以使其正常化，是HD和其他神经退行性疾病的一个潜在治疗途径。
