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

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. The corticostriatal dysfunction underlying Huntington's disease remains incompletely understood. Here, the authors find increased intratelencephalic connectivity resulting from deficient cholinergic transmission in a mouse model of Huntington's disease.

Automated summary

Using a mouse model of Huntington's disease, the authors found increased connectivity in the corticostriatal pathway due to deficient cholinergic transmission. Lowering mutant huntingtin specifically in striatal cholinergic interneurons normalized the connectivity, providing evidence for a key node in the network underlying corticostriatal pathophysiology in Huntington's disease.