Abstract
BackgroundHuntington’s disease (HD) is a dominantly inherited neurodegenerative disorder that affects cognitive and motor abilities by primarily targeting the striatum and cerebral cortex. HD is caused by a mutation elongating the CAG repeats within the Huntingtin gene, resulting in HTT protein misfolding. Although the genetic cause of HD has been established, the specific susceptibility of neurons within various brain structures has remained elusive. Microglia, which are the brain’s resident macrophages, have emerged as important players in neurodegeneration. Nevertheless, few studies have examined their implication in HD.MethodsTo provide novel insights, we investigated the maturation and dysfunction of striatal microglia using the R6/2 mouse model of HD. This transgenic model, which presents with 120+/-5 CAG repeats, displays progressive motor deficits beginning at 6 weeks of age, with full incapacitation by 13 weeks. We studied microglial morphology, phagocytic capacity, and synaptic contacts in the striatum of R6/2 versus wild-type (WT) littermates at 3, 10, and 13 weeks of age, using a combination of light and transmission electron microscopy. We also reconstructed dendrites and determined synaptic density within the striatum of R6/2 and WT littermates, at nanoscale resolution using focused ion beam scanning electron microscopy.ResultsAt 3 weeks of age, prior to any known motor deficits, microglia in R6/2 animals displayed a more mature morphological phenotype than WT animals. Microglia from R6/2 mice across all ages also demonstrated increased phagocytosis, as revealed by light microscopy and transmission electron microscopy. Furthermore, microglial processes from 10-week-old R6/2 mice made fewer contacts with synaptic structures than microglial processes in 3-week-old R6/2 mice and age-matched WT littermates. Synaptic density was not affected by genotype at 3 weeks of age but increased with maturation in WT mice. The location of synapses was lastly modified in R6/2 mice compared with WT controls, from targeting dendritic spines to dendritic trunks at both 3 and 10 weeks of age.ConclusionsThese findings suggest that microglia may play an intimate role in synaptic alteration and loss during HD pathogenesis.
Highlights
Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder that affects cognitive and motor abilities by primarily targeting the striatum and cerebral cortex
While total synaptic input onto dendrites was not reduced in 3-weekold animals, we found that synaptic inputs onto dendrites in the dorsomedial striatum of R6/2 animals were more likely to make en face synapses, targeting dendritic trunks instead of dendritic spines
Microglial morphological maturation is accelerated in the R6/2 mouse model In order to investigate microglial maturation and function in the R6/2 mouse model of HD, we performed Ionized calcium binding adaptor molecule 1 (IBA1) immunostaining followed by densitometric analysis in the striatum of 3-week, 10-week, and 13-week-old animals (Fig. 1a–f)
Summary
Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder that affects cognitive and motor abilities by primarily targeting the striatum and cerebral cortex. Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder characterized by loss of motor control, accompanied by cognitive and psychiatric impairments [1]. It is caused by a CAG repeat expansion within exon 1 of the huntingtin (HTT) gene [2], which is ubiquitously expressed across the body and is required for normal development [3, 4]. Several animal models, including the R6/2 mouse, have been generated to study the effects of mHTT in the brain [8] These animals express exon 1 of human HTT with ~ 120–150 CAG repeats under its endogenous promoter. Disease onset in these animals is between 6 and 9 weeks of age and animals generally die between 12 and 14 weeks of age [8]
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