Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington s disease
(2023) In Proceedings of the National Academy of Sciences of the United States of America 120(24).- Abstract
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... (More)
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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- author
- Villanueva, Carlos Benitez ; Stephensen, Hans J.T. ; Mokso, Rajmund LU ; Benraiss, Abdellatif ; Sporring, Jon and Goldman, Steven A.
- organization
- publishing date
- 2023
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- astrocyte, Huntington s disease, neurodegenerative disease, rabies tracing, synapse
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 120
- issue
- 24
- article number
- e2210719120
- publisher
- National Academy of Sciences
- external identifiers
-
- pmid:37279261
- scopus:85161101365
- ISSN
- 0027-8424
- DOI
- 10.1073/pnas.2210719120
- language
- English
- LU publication?
- yes
- id
- 4093ef08-9f8c-4d11-bf4d-9546dca7c3be
- date added to LUP
- 2023-08-15 14:12:53
- date last changed
- 2024-04-20 01:40:07
@article{4093ef08-9f8c-4d11-bf4d-9546dca7c3be,
abstract = {{<p>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.</p>}},
author = {{Villanueva, Carlos Benitez and Stephensen, Hans J.T. and Mokso, Rajmund and Benraiss, Abdellatif and Sporring, Jon and Goldman, Steven A.}},
issn = {{0027-8424}},
keywords = {{astrocyte; Huntington s disease; neurodegenerative disease; rabies tracing; synapse}},
language = {{eng}},
number = {{24}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences of the United States of America}},
title = {{Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington s disease}},
url = {{http://dx.doi.org/10.1073/pnas.2210719120}},
doi = {{10.1073/pnas.2210719120}},
volume = {{120}},
year = {{2023}},
}