Cholinergic deficits selectively boost cortical intratelencephalic control of the striatum in Huntington’s disease

Abstract Huntington’s disease (HD) is a progressive, neurodegenerative disease caused by a CAG triplet expansion in the huntingtin gene. Although corticostriatal dysfunction has long been implicated in HD, the determinants and pathway specificity of this pathophysiology remain a matter of speculation. To help fill this gap, the zQ175+/- knockin mouse model of HD was studied using approaches that allowed optogenetic interrogation of intratelencephalic (IT) and pyramidal tract (PT) connections with principal striatal spiny projection neurons (SPNs). These studies revealed that the connectivity of IT, but not PT, neurons with direct and indirect pathway SPNs increased in early symptomatic zQ175+/- HD mice. This enhancement was attributable to reduced inhibitory control of IT terminals by striatal cholinergic interneurons (ChIs). Lowering mutant huntingtin selectively in ChIs with a virally-delivered zinc finger repressor protein normalized striatal acetylcholine release and IT functional connectivity – revealing a novel node in the network underlying corticostriatal pathophysiology in HD.

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Enhanced GABAergic Inhibition of Cholinergic Interneurons in the zQ175+/− Mouse Model of Huntington's Disease

Frontiers in Systems Neuroscience ◽

10.3389/fnsys.2020.626412 ◽

2021 ◽

Vol 14 ◽

Author(s):

Sean Austin O. Lim ◽

D. James Surmeier

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Ex Vivo ◽

Brain Slices ◽

Projection Neurons ◽

Gabaergic Inhibition ◽

Indirect Pathway ◽

Cholinergic Interneurons ◽

Specific Alteration

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that initially manifests itself in the striatum. How intrastriatal circuitry is altered by the disease is poorly understood. To help fill this gap, the circuitry linking spiny projection neurons (SPNs) to cholinergic interneurons (ChIs) was examined using electrophysiological and optogenetic approaches in ex vivo brain slices from wildtype mice and zQ175+/− models of HD. These studies revealed a severalfold enhancement of GABAergic inhibition of ChIs mediated by collaterals of indirect pathway SPNs (iSPNs), but not direct pathway SPNs (dSPNs). This cell-specific alteration in synaptic transmission appeared in parallel with the emergence of motor symptoms in the zQ175+/− model. The adaptation had a presynaptic locus, as it was accompanied by a reduction in paired-pulse ratio but not in the postsynaptic response to GABA. The alterations in striatal GABAergic signaling disrupted spontaneous ChI activity, potentially contributing to the network dysfunction underlying the hyperkinetic phase of HD.

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Dysregulation of the basal ganglia indirect pathway prior to cell loss in the Q175 mouse model of Huntington's disease

10.1101/2021.01.06.425589 ◽

2021 ◽

Author(s):

Joshua Callahan ◽

David L Wokosin ◽

Mark D Bevan

Keyword(s):

Basal Ganglia ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Ex Vivo ◽

Cell Loss ◽

Projection Neurons ◽

Indirect Pathway ◽

Cortical Input ◽

Psychomotor Symptoms

The psychomotor symptoms of Huntington's disease (HD) are linked to degeneration of the basal ganglia indirect pathway. To determine how this pathway is perturbed prior to cell loss, optogenetic- and reporter-guided electrophysiological interrogation approaches were applied to early symptomatic 6-month-old Q175 HD mice. Although cortical activity was unaffected, indirect pathway striatal projection neurons were hypoactive in vivo, consistent with reduced cortical input strength and dendritic excitability. Downstream parvalbumin-expressing prototypic external globus pallidus (GPe) neurons were hyperactive in vivo and exhibited elevated autonomous firing ex vivo. Optogenetic inhibition of prototypic GPe neurons ameliorated the abnormal hypoactivity of postsynaptic subthalamic nucleus (STN) and putative arkypallidal neurons in vivo. In contrast to STN neurons, autonomous arkypallidal activity was unimpaired ex vivo. Together with previous studies, these findings demonstrate that basal ganglia indirect pathway neurons are highly dysregulated in Q175 mice through changes in presynaptic activity and/or intrinsic properties 6-12 months before cell loss.

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Cholinergic interneurons in the Q140 knockin mouse model of Huntington's disease: Reductions in dendritic branching and thalamostriatal input

The Journal of Comparative Neurology ◽

10.1002/cne.24013 ◽

2016 ◽

Vol 524 (17) ◽

pp. 3518-3529 ◽

Cited By ~ 17

Author(s):

Yun-Ping Deng ◽

Anton Reiner

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Cholinergic Interneurons ◽

Dendritic Branching ◽

Knockin Mouse

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Faculty Opinions recommendation of TR-FRET-based duplex immunoassay reveals an inverse correlation of soluble and aggregated mutant huntingtin in huntington's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717951315.793456621 ◽

2012 ◽

Author(s):

Roger Barker ◽

Wei-Li Kuan

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Inverse Correlation ◽

Mutant Huntingtin

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Faculty Opinions recommendation of Mutant huntingtin fragmentation in immune cells tracks Huntington's disease progression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717960625.793464988 ◽

2012 ◽

Author(s):

Stefano Di Donato

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Progression ◽

Immune Cells ◽

Mutant Huntingtin

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Identification of Full-Length Wild-Type and Mutant Huntingtin Interacting Proteins by Crosslinking Immunoprecipitation in Mice Brain Cortex

Journal of Huntington s Disease ◽

10.3233/jhd-210476 ◽

2021 ◽

pp. 1-13

Author(s):

Karen A. Sap ◽

Arzu Tugce Guler ◽

Aleksandra Bury ◽

Dick Dekkers ◽

Jeroen A.A. Demmers ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Brain Cortex ◽

Full Length ◽

Biological Processes ◽

Interacting Proteins ◽

Mutant Huntingtin ◽

Wild Type ◽

Mutant Huntingtin Protein ◽

Mice Brain

Background: Huntington’s disease is a neurodegenerative disorder caused by a CAG expansion in the huntingtin gene, resulting in a polyglutamine expansion in the ubiquitously expressed mutant huntingtin protein. Objective: Here we set out to identify proteins interacting with the full-length wild-type and mutant huntingtin protein in the mice cortex brain region to understand affected biological processes in Huntington’s disease pathology. Methods: Full-length huntingtin with 20 and 140 polyQ repeats were formaldehyde-crosslinked and isolated via their N-terminal Flag-tag from 2-month-old mice brain cortex. Interacting proteins were identified and quantified by label-free liquid chromatography-mass spectrometry (LC-MS/MS). Results: We identified 30 interactors specific for wild-type huntingtin, 14 interactors specific for mutant huntingtin and 14 shared interactors that interacted with both wild-type and mutant huntingtin, including known interactors such as F8a1/Hap40. Syt1, Ykt6, and Snap47, involved in vesicle transport and exocytosis, were among the proteins that interacted specifically with wild-type huntingtin. Various other proteins involved in energy metabolism and mitochondria were also found to associate predominantly with wild-type huntingtin, whereas mutant huntingtin interacted with proteins involved in translation including Mapk3, Eif3h and Eef1a2. Conclusion: Here we identified both shared and specific interactors of wild-type and mutant huntingtin, which are involved in different biological processes including exocytosis, vesicle transport, translation and metabolism. These findings contribute to the understanding of the roles that wild-type and mutant huntingtin play in a variety of cellular processes both in healthy conditions and Huntington’s disease pathology.

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