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bioRxiv · 10.1101/2023.09.06.556580

Activin A targets extrasynaptic NMDA receptors to improve neuronal and behavioral deficits in a mouse model of Huntington disease

Nassrallah, W. B.·Ramandi, D.·Cheng, J.·Oh, J.·Mackay, J.·Sepers, M. D.·Lau, D.·Bading, H.·Raymond, L.
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Abstract

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.

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Nassrallah, W. B., Ramandi, D., Cheng, J., Oh, J., Mackay, J., Sepers, M. D., Lau, D., Bading, H., Raymond, L.. 2023-09-06. Activin A targets extrasynaptic NMDA receptors to improve neuronal and behavioral deficits in a mouse model of Huntington disease. https://doi.org/10.1101/2023.09.06.556580

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