Striatal S1R is upregulated in both mice and patients with advanced but not early HD. Pridopidine stabilizes MSN spines in aging YAC128 corticostriatal co-cultures via S1R. Pridopidine normalizes synaptic and ER Ca2 + homeostasis in YAC128 MSNs. Pridopidine upregulates calbindin and homer1a, which are downregulated in HD models. The therapeutic effects of pridopidine in HD treatment are likely mediated by the S1R.