Presymptomatic targeted circuit manipulation for ameliorating Huntington’s disease pathogenesis
Ebenezer C. Ikefuama,
Ashley N. Slaviero,
Alexander D. Silvagnoli,
Emmanuel L. Crespo,
Raegan Schalau,
Madison Gott,
Maya O. Tree,
Gary L. Dunbar,
Julien Rossignol,
Ute Hochgeschwender
Affiliations
Ebenezer C. Ikefuama
Program in Neuroscience, Central Michigan University, Mount Pleasant, MI 48859, USA
Ashley N. Slaviero
Biochemistry, Cell and Molecular Biology Program, Central Michigan University, Mount Pleasant, MI 48859, USA
Alexander D. Silvagnoli
Program in Neuroscience, Central Michigan University, Mount Pleasant, MI 48859, USA
Emmanuel L. Crespo
Biochemistry, Cell and Molecular Biology Program, Central Michigan University, Mount Pleasant, MI 48859, USA
Raegan Schalau
Program in Neuroscience, Central Michigan University, Mount Pleasant, MI 48859, USA
Madison Gott
Program in Neuroscience, Central Michigan University, Mount Pleasant, MI 48859, USA
Maya O. Tree
College of Medicine, Central Michigan University, Mount Pleasant, MI 48859, USA
Gary L. Dunbar
Department of Psychology, Central Michigan University, Mount Pleasant, MI 48859, USA
Julien Rossignol
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; College of Medicine, Central Michigan University, Mount Pleasant, MI 48859, USA
Ute Hochgeschwender
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; College of Medicine, Central Michigan University, Mount Pleasant, MI 48859, USA; Corresponding author
Summary: 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.
