A Toolkit for Targeted Neuromodulation of Striatal Direct Pathway Neurons Rescues Parkinsonian Motor Deficits in Mice.

Striatal medium spiny neurons expressing D1 dopamine receptors (D1-MSNs) are a key component in the direct pathway of the basal ganglia and exhibit chronically suppressed activity in Parkinson's disease. To enable selective anatomical and functional interrogation of D1-MSNs, we developed an adeno-associated virus (AAV) toolkit that achieved robust and selective transgene expression in D1-MSNs through retrograde transduction of their substantia nigra axons. We first screened an AAV9 capsid insertion library and identified variants with markedly enhanced retrograde access to D1-MSNs. Next, we engineered a series of enhancers and demonstrate that they drive strong and specific gene expression in D1-MSNs after retrograde transduction in both mice and a macaque. Importantly, we demonstrate that our toolkit enables targeted modulation of the direct pathway, eliciting pathway-specific behaviors and rescuing motor deficits in a murine model of Parkinson's disease. These findings highlight the utility of our D1-MSN-targeting tools for basic and translational research.