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Publication : Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington's disease.

First Author  Villanueva CB Year  2023
Journal  Proc Natl Acad Sci U S A Volume  120
Issue  24 Pages  e2210719120
PubMed ID  37279261 Mgi Jnum  J:349223
Mgi Id  MGI:7491547 Doi  10.1073/pnas.2210719120
Citation  Villanueva CB, et al. (2023) Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington's disease. Proc Natl Acad Sci U S A 120(24):e2210719120
abstractText  Astroglial dysfunction contributes to the pathogenesis of Huntington's disease (HD), and glial replacement can ameliorate the 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 turboRFP-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 nanometer-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 the astroglial engagement and sequestration of MSN synapses enable the high synaptic and extrasynaptic levels of glutamate and K(+) that underlie striatal hyperexcitability in 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.
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