Activin A targets extrasynaptic NMDA receptors to ameliorate neuronal and behavioral deficits in a mouse model of Huntington disease
Cortical-striatal synaptic dysfunction, including enhanced toxic signaling by extrasynaptic N-methyl-d-aspartate receptors (eNMDARs), precedes neurodegeneration in Huntington disease (HD). A previous study showed Activin A, whose transcription is upregulated by calcium influx via synaptic NMDARs, su...
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| Hauptverfasser: | , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
20 November 2023
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| In: |
Neurobiology of disease
Year: 2023, Jahrgang: 189, Pages: 1-10 |
| ISSN: | 1095-953X |
| DOI: | 10.1016/j.nbd.2023.106360 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.nbd.2023.106360 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0969996123003765 
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| Verfasserangaben: | Wissam B. Nassrallah, Daniel Ramandi, Judy Cheng, Jean Oh, James Mackay, Marja D. Sepers, David Lau, Hilmar Bading, Lynn A. Raymond |
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| 520 | |a Cortical-striatal synaptic dysfunction, including enhanced toxic signaling by extrasynaptic N-methyl-d-aspartate receptors (eNMDARs), precedes neurodegeneration in Huntington disease (HD). A previous study showed Activin A, whose transcription is upregulated by calcium influx via synaptic NMDARs, suppresses eNMDAR signaling. Therefore, we examined the role of Activin A in the YAC128 HD mouse model, comparing it to wild-type controls. We found decreased Activin A secretion in YAC128 cortical-striatal co-cultures, while Activin A overexpression in this model rescued altered eNMDAR expression. Striatal overexpression of Activin A in vivo improved motor learning on the rotarod task, and normalized striatal neuronal eNMDAR-mediated currents, membrane capacitance and spontaneous excitatory postsynaptic current frequency in the YAC128 mice. These results support the therapeutic potential of Activin A signaling and targeting eNMDARs to restore striatal neuronal health and ameliorate behavioral deficits in HD. | ||
| 650 | 4 | |a Glutamatergic neurotransmission | |
| 650 | 4 | |a Patch clamp recording | |
| 650 | 4 | |a Striatal medium-sized spiny neuron | |
| 650 | 4 | |a Synapse | |
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