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

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. [2013] 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. (C) 2016 Wiley Periodicals, Inc.