Striatal spatial heterogeneity, clustering, and white matter association of GFAP+ astrocytes in a mouse model of Huntington’s disease

Abstract

IntroductionHuntington’s disease (HD) is a neurodegenerative disease that primarily affects the striatum, a brain region that controls movement and some forms of cognition. Neuronal dysfunction and loss in HD is accompanied by increased astrocyte density and astrocyte pathology. Astrocytes are a heterogeneous population classified into multiple subtypes depending on the expression of different gene markers. Studying whether mutant Huntingtin (HTT) alters specific subtypes of astrocytes is necessary to understand their relative contribution to HD.MethodsHere, we studied whether astrocytes expressing two different markers; glial fibrillary acidic protein (GFAP), associated with astrocyte activation, and S100 calcium-binding protein B (S100B), a marker of matured astrocytes and inflammation, were differentially altered in HD.ResultsFirst, we found three distinct populations in the striatum of WT and symptomatic zQ175 mice: GFAP+, S100B+, and dual GFAP+S100B+. The number of GFAP+ and S100B+ astrocytes throughout the striatum was increased in HD mice compared to WT, coinciding with an increase in HTT aggregation. Overlap between GFAP and S100B staining was expected, but dual GFAP+S100B+ astrocytes only accounted for less than 10% of all tested astrocytes and the number of GFAP+S100B+ astrocytes did not differ between WT and HD, suggesting that GFAP+ astrocytes and S100B+ astrocytes are distinct types of astrocytes. Interestingly, a spatial characterization of these astrocyte subtypes in HD mice showed that while S100B+ were homogeneously distributed throughout the striatum, GFAP+ preferentially accumulated in “patches” in the dorsomedial (dm) striatum, a region associated with goal-directed behaviors. In addition, GFAP+ astrocytes in the dm striatum of zQ175 mice showed increased clustering and association with white matter fascicles and were preferentially located in areas with low HTT aggregate load.DiscussionIn summary, we showed that GFAP+ and S100B+ astrocyte subtypes are distinctly affected in HD and exist in distinct spatial arrangements that may offer new insights to the function of these specific astrocytes subtypes and their potential implications in HD pathology.

Distinct forebrain regions define a dichotomous astrocytic profile in multiple system atrophy

“…There is evidence that striatal astrocytes demonstrate altered transcriptomic profiles in inflammatory environment [ 67 ] associated with impaired homeostatic functions for calcium and glutamate signaling [ 68 ]. Distinct populations of astrocytes were identified in a HD mouse model exhibiting variable transcriptional phenotypes in the cortex reflecting a rather protective phenotype consistent with our findings [ 69 , 70 ]. Another study characterizing astrocytes by single nuclei sorting in the prefrontal cortex, most severely affected in AD patients, revealed decreased homeostatic and increased levels of inflammatory transcripts [ 71 ].…”

Focused Ultrasound-Mediated Disruption of the Blood–Brain Barrier for AAV9 Delivery in a Mouse Model of Huntington’s Disease

“…Quantification of astrocyte activation revealed significantly higher levels of GFAP expression in the FUS-treated and un-treated striatum of zQ175 12-month mice compared to the zQ175 6-month, zQ175 2-month, and WT groups. The higher levels of astrocytic activation in the oldest HD cohort are in line with previous studies that demonstrate that zQ175 mice exhibit increased astrocyte pathology at later stages of disease progression [83]. All mouse groups had, on average, higher GFAP expression in the FUS-targeted striatum compared to the non-targeted striatum, but this difference did not rise to the level of significance within individual groups.…”

“…A vast majority of FUS-AAV studies have been performed in WT mice, but here we treated zQ175 mice at different ages. These mice show upregulated GFAP expression as HD progresses in this model [ 83 ]. Increased GFAP and Iba1 expression have been noted following FUS + MB-mediated BBB opening [ 64 , 65 , 66 , 97 ].…”