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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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Main Authors: Nassrallah, Wissam B. (Author) , Ramandi, Daniel (Author) , Cheng, Judy (Author) , Oh, Jean (Author) , Mackay, James (Author) , Sepers, Marja D. (Author) , Lau, David (Author) , Bading, Hilmar (Author) , Raymond, Lynn A. (Author)
Format: Article (Journal)
Language:English
Published: 20 November 2023
In: Neurobiology of disease
Year: 2023, Volume: 189, Pages: 1-10
ISSN:1095-953X
DOI:10.1016/j.nbd.2023.106360
Online Access: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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Author Notes: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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Summary: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.
Item Description:Gesehen am 14.05.2024
Physical Description:Online Resource
ISSN:1095-953X
DOI:10.1016/j.nbd.2023.106360

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