Restoring cortical disinhibition improves Huntington's disease phenotypes.

Overview

1. Department of Neurobiology, Center for Neural Circuits and Behavior, University of California San Diego,La Jolla, CA USA
2. Department of Molecules–Signaling–Development, Max Planck Institute for Biological Intelligence,Martinsried, Germany
3. Molecular Neurodegeneration Group, Max Planck Institute for Biological Intelligence,Martinsried, Germany
4. Department of Neurosciences, University of California San Diego,La Jolla, CA USA
5. Center for Anatomy, Faculty of Medicine and University Hospital Cologne, University of Cologne,Cologne, Germany
6. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne,Cologne, Germany
7. Institute of Anatomy and Cell Biology, University of Würzburg,Würzburg, Germany
8. Halıcıoğlu Data Science Institute, University of California San Diego,La Jolla, CA USA

Abstract

Huntington’s disease (HD) is a devastating movement disorder without a cure at present1. Although the monogenic basis of HD is well defined2, the complex downstream effects that underlie behavioural symptoms are poorly understood. These effects include cortical dysfunction3,4, yet the roles of specific cortical neuronal subtypes in HD symptoms remain largely unexplored. Here we used longitudinal in vivo two-photon calcium imaging to examine the activity of three cortical inhibitory neuron (IN) subtypes and excitatory corticostriatal (CStr) projection neurons in the motor cortex of the transgenic R6/2 HD mouse model throughout disease progression. We found that motor deficits in R6/2 mice were accompanied by neuron subtype-specific abnormalities in movement-related activity. This included marked hypoactivity of vasoactive intestinal peptide (VIP)-INs and CStr neurons, which was also observed in the knock-in zQ175DN HD mouse model. Optogenetic activation of VIP-INs in R6/2 mice restored healthy levels of activity in VIP-INs and their downstream CStr neurons and ameliorated motor deficits in R6/2 mice; behavioural improvements persisted for days after stimulation. Our findings highlight cortical INs as a potential therapeutic target for HD.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

No file of the authors' code could be read here: it is described below, and read at its source.

Code availability

The code used in this study is available via Zenodo (10.5281/zenodo.20750675)51 or from the corresponding authors (S.B., I.D. and T.K.) on request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data availability

Source data are provided with this paper, as well as on Zenodo (10.5281/zenodo.20750675)51. Additional datasets supporting the current work are available from the corresponding authors (S.B., I.D. and T.K.) on reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 3 keywords, 17 MeSH terms, 1 funder, 51 references.

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This paper

Blumenstock, S., Arakelyan, D., del Grosso, N., Schneider, S., Shao, Y., Gjoni, E., Klein, R., Dudanova, I., & Komiyama, T. (2026). Restoring cortical disinhibition improves Huntington's disease phenotypes. Nature, 655(8125), 1262-1270. https://doi.org/10.1038/s41586-026-10671-9

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