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Cholinergic deficits selectively boost cortical intratelencephalic control of striatum in male Huntington’s disease model mice

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Listed:
  • Tristano Pancani

    (Northwestern University)

  • Michelle Day

    (Northwestern University)

  • Tatiana Tkatch

    (Northwestern University)

  • David L. Wokosin

    (Northwestern University)

  • Patricia González-Rodríguez

    (Northwestern University
    Department of Medical Physiology and Biophysics Instituto de Biomedicina de Sevilla (IBiS))

  • Jyothisri Kondapalli

    (Northwestern University)

  • Zhong Xie

    (Northwestern University)

  • Yu Chen

    (Northwestern University)

  • Vahri Beaumont

    (CHDI Management/CHDI Foundation)

  • D. James Surmeier

    (Northwestern University)

Abstract

Huntington’s disease (HD) is a progressive, neurodegenerative disease caused by a CAG triplet expansion in huntingtin. Although corticostriatal dysfunction has long been implicated in HD, the determinants and pathway specificity of this pathophysiology are not fully understood. Here, using a male zQ175+/− knock-in mouse model of HD we carry out optogenetic interrogation of intratelencephalic and pyramidal tract synapses with principal striatal spiny projection neurons (SPNs). These studies reveal that the connectivity of intratelencephalic, but not pyramidal tract, neurons with direct and indirect pathway SPNs increased in early symptomatic zQ175+/− HD mice. This enhancement was attributable to reduced pre-synaptic inhibitory control of intratelencephalic terminals by striatal cholinergic interneurons. Lowering mutant huntingtin selectively in striatal cholinergic interneurons with a virally-delivered zinc finger repressor protein normalized striatal acetylcholine release and intratelencephalic functional connectivity, revealing a node in the network underlying corticostriatal pathophysiology in a HD mouse model.

Suggested Citation

  • Tristano Pancani & Michelle Day & Tatiana Tkatch & David L. Wokosin & Patricia González-Rodríguez & Jyothisri Kondapalli & Zhong Xie & Yu Chen & Vahri Beaumont & D. James Surmeier, 2023. "Cholinergic deficits selectively boost cortical intratelencephalic control of striatum in male Huntington’s disease model mice," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36556-3
    DOI: 10.1038/s41467-023-36556-3
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    References listed on IDEAS

    as
    1. Michael Eisenstein, 2018. "CRISPR takes on Huntington’s disease," Nature, Nature, vol. 557(7707), pages 42-43, May.
    2. Nuo Li & Tsai-Wen Chen & Zengcai V. Guo & Charles R. Gerfen & Karel Svoboda, 2015. "A motor cortex circuit for motor planning and movement," Nature, Nature, vol. 519(7541), pages 51-56, March.
    3. Tim Fieblinger & Steven M. Graves & Luke E. Sebel & Cristina Alcacer & Joshua L. Plotkin & Tracy S. Gertler & C. Savio Chan & Myriam Heiman & Paul Greengard & M. Angela Cenci & D. James Surmeier, 2014. "Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia," Nature Communications, Nature, vol. 5(1), pages 1-15, December.
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