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bioRxiv · 10.1101/2022.12.06.519168

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

Benitez, C.·Stephensen, H. J.·Benraiss, A.·Mokso, R.·Sporring, J.·Goldman, S.
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Abstract

Astroglial dysfunction contributes to the pathogenesis of Huntingtons 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. Significance StatementAstrocytic physiological dysfunction contributes to development of the neurodegenerative phenotype in Huntingtons disease (HD), but the structural correlates to this dysfunction are unclear. Here, we used a combination of viral tracing, phenotype-specific tagging, and ultrastructural modalities to reconstruct and study HD synapses at nm scale, in the neostriata of HD mice. We discovered significant impairment in the glial engagement of mature striatal synapses. In light of the known deficiencies in glutamate and potassium uptake by HD astrocytes, these findings suggest the potential for leakage of excitatory synaptic contents during neurotransmission, and hance a structural basis for neuronal hyperexcitability in HD. More broadly, our data suggest that astrocytic structural pathology may causally contribute to those neurodegenerative disorders associated with central hyperexcitability.

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Benitez, C., Stephensen, H. J., Benraiss, A., Mokso, R., Sporring, J., Goldman, S.. 2022-12-06. Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington disease. https://doi.org/10.1101/2022.12.06.519168

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