Cholinergic Deficits Selectively Boost Cortical Intratelencephalic Control of Striatum in Male Huntington's Disease Model Mice

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Mar 14

PMID 36914640

Authors

Tristano Pancani

Michelle Day

Tatiana Tkatch

David L Wokosin

Patricia Gonzalez-Rodriguez

Jyothisri Kondapalli

Zhong Xie

Yu Chen

Vahri Beaumont

D James Surmeier

Affiliations

Soon will be listed here.

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.

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