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

Tristano Pancani, Michelle Day, Tatiana Tkatch, David L. Wokosin, Patricia González-Rodríguez, Jyothisri Kondapalli, Zhong Xie, Yu Chen, Vahri Beaumont and D. James Surmeier ()
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Tristano Pancani: Northwestern University
Michelle Day: Northwestern University
Tatiana Tkatch: Northwestern University
David L. Wokosin: Northwestern University
Patricia González-Rodríguez: Northwestern University
Jyothisri Kondapalli: Northwestern University
Zhong Xie: Northwestern University
Yu Chen: Northwestern University
Vahri Beaumont: CHDI Management/CHDI Foundation
D. James Surmeier: Northwestern University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36556-3

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