Cortical-striatal synaptic dysfunction, including enhanced toxic signaling by extrasynaptic Toddler Clothing 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 Cream Blush 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.