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. 2016 Dec 1;524(17):3518-3529.
doi: 10.1002/cne.24013. Epub 2016 Jun 6.

Cholinergic Interneurons in the Q140 Knockin Mouse Model of Huntington's Disease: Reductions in Dendritic Branching and Thalamostriatal Input

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Free PMC article

Cholinergic Interneurons in the Q140 Knockin Mouse Model of Huntington's Disease: Reductions in Dendritic Branching and Thalamostriatal Input

Yun-Ping Deng et al. J Comp Neurol. .
Free PMC article

Abstract

We have previously found that thalamostriatal axodendritic terminals are reduced as early as 1 month of age in heterozygous Q140 HD mice (Deng et al. [] Neurobiol Dis 60:89-107). Because cholinergic interneurons are a major target of thalamic axodendritic terminals, we examined the VGLUT2-immunolabeled thalamic input to striatal cholinergic interneurons in heterozygous Q140 males at 1 and 4 months of age, using choline acetyltransferase (ChAT) immunolabeling to identify cholinergic interneurons. Although blinded neuron counts showed that ChAT+ perikarya were in normal abundance in Q140 mice, size measurements indicated that they were significantly smaller. Sholl analysis further revealed the dendrites of Q140 ChAT+ interneurons were significantly fewer and shorter. Consistent with the light microscopic data, ultrastructural analysis showed that the number of ChAT+ dendritic profiles per unit area of striatum was significantly decreased in Q140 striata, as was the abundance of VGLUT2+ axodendritic terminals making synaptic contact with ChAT+ dendrites per unit area of striatum. The density of thalamic terminals along individual cholinergic dendrites was, however, largely unaltered, indicating that the reduction in the areal striatal density of axodendritic thalamic terminals on cholinergic neurons was due to their dendritic territory loss. These results show that the abundance of thalamic input to individual striatal cholinergic interneurons is reduced early in the life span of Q140 mice, raising the possibility that this may occur in human HD as well. Because cholinergic interneurons differentially affect striatal direct vs. indirect pathway spiny projection neurons, their reduced thalamic excitatory drive may contribute to early abnormalities in movement in HD. J. Comp. Neurol. 524:3518-3529, 2016. © 2016 Wiley Periodicals, Inc.

Keywords: AB_2301731; AB_90650; Huntington's disease; cholinergic interneurons; corticostriatal; pathology; premanifest; striatum; thalamostriatal.

Figures

Figure 1
Figure 1
Images of ChAT+ cholinergic interneurons in the right striatum of WT (A) and Q140 (B) mice, and box-and-whicker plots comparing their mean abundance per striatum at the levels assessed (C) and comparing their perikaryal diameter (D) between WT and mutant mice. No significant difference in the abundance of striatal ChAT+ perikarya was found between Q140 and WT mice (C), but the perikaryal diameter was slightly but significantly less (asterisk) in the mutants.
Figure 2
Figure 2
Images of ChAT+ cholinergic interneurons in the striatum of WT (A) and Q140 (B) mice, showing the slightly smaller size and lessened dendritic branching in the Q140 mice.
Figure 3
Figure 3
Representative camera lucida drawings of ChAT+ cholinergic interneurons at high power in the striatum of WT (A) and Q140 (B) mice, a box-and-whicker plot showing total dendrite intersections (C), and a graph showing dendrite intersections as a function of distance from the soma (D) in WT and mutant mice based on Sholl analysis. The results show that dendritic arborizations of ChAT+ interneurons were significantly decreased in Q140 heterozygous mice. One outlier is evident for the WT mice in C.
Figure 4
Figure 4
EM images with cholinergic processes highlighted, showing that fewer ChAT+ profiles are typically present per unit area in Q140 striatum than in WT striatum.
Figure 5
Figure 5
Representative EM images showing VGLUT2+/ChAT+ double-immunolabeling in striatum in WT mice at 1 month of age. Image A shows VGLUT2+ immunolabeled terminals (arrow) and ChAT+ immunolabeled dendrites (den). Image B presents a high power view of the framed selection in image A, showing a VGLUT+ synaptic terminal on a ChAT+ dendrite.
Figure 6
Figure 6
Representative EM images of VGLUT2+/ChAT double-immunolabeling in striatum in WT (A) and Q140 (B) mice at 1 month of age. VGLUT2+ immunolabeled synaptic terminals are indicated by arrows. ChAT+ dendrites are indicated by the abbreviation “den”. Both images are at the same magnification. The areal abundance of VGLUT2+ synaptic terminals on ChAT+ dendrites was determined for Q140 and WT mice at 1 and 4 months of age, and found to be less.

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