A Toolkit for Targeted Neuromodulation of Striatal Direct Pathway Neurons Rescues Parkinsonian Motor Deficits in Mice.
A Toolkit for Targeted Neuromodulation of Striatal Direct Pathway Neurons Rescues Parkinsonian Motor Deficits in Mice.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Shenzhen, CN · Author affiliation
Department of Anesthesiology, Women and Children's Medical Center, Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, China.Location evidence
HK · Author affiliation · country only
Shenzhen Key Laboratory For Molecular Biology of Neural Development, Shenzhen Technological Research Center for Primate Translational Medicine, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.Location evidence
CN · Author affiliation · country only
Faculty of Health Sciences, University of Macau, Macau SAR, China.Location evidence
Beijing, CN · Author affiliation
Children's Medical Center, Peking University First Hospital, Beijing, China.Location evidence
Shantou, CN · Author affiliation
Department of Anesthesia, Affiliated Shenzhen Children's Hospital of Shantou University Medical College, Shenzhen, Guangdong, China.Location evidence
Hangzhou, CN · Author affiliation
Department of Neurology, The Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China.Location evidence
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Original abstract
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.