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Dysfunctional Calcium and Glutamate Signaling in Striatal Astrocytes from Huntington's Disease Model Mice
Open accessAbstract
Astrocytes tile the entire CNS, but their functions within neural circuits in health and disease remain incompletely understood. We used genetically encoded Ca 2+ and glutamate indicators to explore the rules for astrocyte engagement in the corticostriatal circuit of adult wild-type (WT) and Huntington's disease (HD) model mice at ages not accompanied by overt astrogliosis (at approximately postnatal days 70–80). WT striatal astrocytes displayed extensive spontaneous Ca 2+ signals, but did not respond to cortical stimulation, implying that astrocytes were largely disengaged from cortical input in healthy tissue. In contrast, in HD model mice, spontaneous Ca 2+ signals were significantly reduced in frequency, duration, and amplitude, but astrocytes responded robustly to cortical stimulation with evoked Ca 2+ signals. These action-potential-dependent astrocyte Ca 2+ signals were mediated by neuronal glutamate release during cortical stimulation, accompanied by prolonged extracellular glutamate levels near astrocytes and tightly gated by Glt1 glutamate transporters. Moreover, dysfunctional Ca 2+ and glutamate signaling that was observed in HD model mice was largely, but not completely, rescued by astrocyte specific restoration of Kir4.1, emphasizing the important contributions of K + homeostatic mechanisms that are known to be reduced in HD model mice. Overall, our data show that astrocyte engagement in the corticostriatal circuit is markedly altered in HD. Such prodromal astrocyte dysfunctions may represent novel therapeutic targets in HD and other brain disorders. SIGNIFICANCE STATEMENT We report how early-onset astrocyte dysfunction without detectable astrogliosis drives disease-related processes in a mouse model of Huntington's disease (HD). The cellular mechanisms involve astrocyte homeostasis and signaling mediated by Kir4.1, Glt1, and Ca 2+ . The data show that the rules for astrocyte engagement in a neuronal circuit are fundamentally altered in a brain disease caused by a known molecular defect and that fixing early homeostasis dysfunction remedies additional cellular deficits. Overall, our data suggest that key aspects of altered striatal function associated with HD may be triggered, at least in part, by dysfunctional astrocytes, thereby providing details of an emerging striatal microcircuit mechanism in HD. Such prodromal changes in astrocytes may represent novel therapeutic targets.
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“Astrocyte Ca2+ dynamics and network responses become aberrant in mouse models of HD53, AD54, and ALS55, possibly contributing to cognitive impairment and neuropathology43,53,56.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [53]
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“Optogenetics25 and designer receptors exclusively activated by designer drugs (DREADDs)25 are potential tools to manipulate reactive astrocytes or to restore their aberrant Ca2+ signaling observed in mouse models of neurodegenerative diseases53–55.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [53]
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The Mystery and Magic of Glia: A Perspective on Their Roles in Health and Disease
Barres, B. A. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.013 · Cited by 1,352
Diversity of astrocyte functions and phenotypes in neural circuits
Khakh, B. S., & Sofroniew, M. V. (2015) · Nature Neuroscience · doi:10.1038/nn.4043 · Cited by 1,239
Self-citationTabrizi, S. J., Langbehn, D. R., Leavitt, B. R., Roos, R. A., Durr, A., Craufurd, D., Kennard, C., Hicks, S. L., Fox, N. C., Scahill, R. I., et al. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70170-x · Cited by 984
An optimized fluorescent probe for visualizing glutamate neurotransmission
Marvin, J., Borghuis, B., Tian, L., Cichon, J., Harnett, M. T., Akerboom, J., Gordus, A., Renninger, S., Chen, T.-W., Bargmann, C., et al. (2013) · Nature Methods · doi:10.1038/nmeth.2333 · Cited by 965
Self-citationPotassium buffering in the central nervous system
Kofuji, P., & Newman, E. A. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.06.008 · Cited by 847
Mechanisms of Disease: astrocytes in neurodegenerative disease
Maragakis, N. J., & Rothstein, J. D. (2006) · Nature Clinical Practice Neurology · doi:10.1038/ncpneuro0355 · Cited by 836
Synchronous Hyperactivity and Intercellular Calcium Waves in Astrocytes in Alzheimer Mice
Kuchibhotla, K. V., Lattarulo, C. R., Hyman, B. T., & Bacskai, B. J. (2009) · Science · doi:10.1126/science.1169096 · Cited by 729
Astrocytes Are Endogenous Regulators of Basal Transmission at Central Synapses
Panatier, A., Vallée, J., Haber, M., Murai, K. K., Lacaille, J.-C., & Robitaille, R. (2011) · Cell · doi:10.1016/j.cell.2011.07.022 · Cited by 650
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Reactive astrocyte nomenclature, definitions, and future directions
Escartin, C., Galea, E., Lakatos, A., O’Callaghan, J. P., Petzold, G. C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00783-4 · Cited by 2,513
Self-citationChai, H., Diaz-Castro, B., Shigetomi, E., Monte, E., Octeau, J. C., Yu, X., Cohn, W., Rajendran, P. S., Vondriska, T. M., Whitelegge, J. P., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.06.029 · Cited by 769
Self-citationFunction and therapeutic value of astrocytes in neurological diseases
Lee, H.-G., Wheeler, M. A., & Quintana, F. J. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00390-x · Cited by 662
Molecular basis of astrocyte diversity and morphology across the CNS in health and disease
Endo, F., Kasai, A., Soto, J. S., Yu, X., Qu, Z., Hashimoto, H., Gradinaru, V., Kawaguchi, R., & Khakh, B. S. (2022) · Science · doi:10.1126/science.adc9020 · Cited by 560
Self-citationFunctional roles of reactive astrocytes in neuroinflammation and neurodegeneration
Patani, R., Hardingham, G. E., & Liddelow, S. A. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00822-1 · Cited by 531
Metadata
- Authors
- Jiang, R., Diaz-Castro, B., Looger, L. L., & Khakh, B. S.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California, Los Angeles (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-03-23
- Volume
- 36
- Issue
- 12
- Pages
- 3453-3470
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4804005
- OpenAlex
- W2307837122
- Cited by
- 237
- References
- 66
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 38 · 2023: 31 · 2022: 22 · 2021: 25 · 2020: 22 · 2019: 30 · 2018: 21 · 2017: 11 · 2016: 12
- FWCI
- 13.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- Howard Hughes Medical Institute
- CHDI Foundation
- National Institutes of Health
- National Institute of Mental Health (MH104069, DP1MH104069)
- National Institute of Neurological Disorders and Stroke (NS060677, R01NS060677)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Huntington's disease, striatal astrocytes, astrocyte calcium signaling, glutamate signaling, corticostriatal circuits, Kir4.1, extracellular glutamate, genetically encoded calcium indicators
- MeSH terms
- Animals, Astrocytes, Calcium, Corpus Striatum, Female, Huntington Disease, Male, Mice, Inbred C57BL, Signal Transduction, Glutamic Acid, Mice
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