A Toolkit for Targeted Neuromodulation of Striatal Direct Pathway Neurons Rescues Parkinsonian Motor Deficits in Mice
Zexuan Hong, Yujing Zhang, Junjiao Zhang, Hanhe Liu, Qiwei Liu, Yanglei Li, Lixin Yang, Lixia Li, Zhongjie Liu, Zhen Yuan, Zhonghua Lu, Yefei Chen, Yuantao Li, Yuwu Jiang, Taian LiuABSTRACT
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.