Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington disease

Astroglial dysfunction contributes to the pathogenesis of Huntington's disease (HD), and glial replacement can ameliorate disease course. To establish the topographic relationship of diseased astrocytes to medium spiny neuron (MSN) synapses in HD, we used 2-photon imaging to map the relationship of tRFP-tagged striatal astrocytes and rabies-traced, EGFP-tagged coupled neuronal pairs, in R6/2 HD and wild-type (WT) mice. The tagged, prospectively-identified corticostriatal synapses were then studied by correlated light electron microscopy followed by serial block-face scanning EM, allowing nm scale assessment of synaptic structure in 3D. By this means, we compared the astrocytic engagement of single striatal synapses in HD and WT brains. R6/2 HD astrocytes exhibited constricted domains, with significantly less coverage of mature dendritic spines than WT astrocytes, despite enhanced engagement of immature, thin spines. These data suggest that disease-dependent changes in astroglial engagement and sequestration of MSN synapses enable the high synaptic and extrasynaptic levels of glutamate and K+ that underlie the striatal hyperexcitability of HD. As such, these data suggest that astrocytic structural pathology may causally contribute to the synaptic dysfunction and disease phenotype of those neurodegenerative disorders characterized by network overexcitation. ### Competing Interest Statement Dr. Goldman is also a part-time employee and stock-holder of Sana Biotechnology (Seattle, WA), and his lab receives sponsored research support from Sana. Dr. Goldman is also a co-founder, advisory board member and stock-holder of CNS2 (Boston, MA). None of the other authors have any known conflicts of interest in regards to this work.