AAV11 enables efficient retrograde targeting of projection neurons and enhances astrocyte-directed transduction

Zengpeng Han, Nengsong Luo, Wenyu Ma, Xiaodong Liu, Yuxiang Cai, Jiaxin Kou, Jie Wang, Lei Li, Siqi Peng, Zihong Xu, Wen Zhang, Yuxiang Qiu, Yang Wu, Chaohui Ye, Kunzhang Lin () and Fuqiang Xu ()
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Zengpeng Han: Chinese Academy of Sciences
Nengsong Luo: Huazhong University of Science and Technology
Wenyu Ma: Chinese Academy of Sciences
Xiaodong Liu: The Chinese University of Hong Kong
Yuxiang Cai: Huazhong University of Science and Technology
Jiaxin Kou: Huazhong University of Science and Technology
Jie Wang: Chinese Academy of Sciences
Lei Li: Chinese Academy of Sciences
Siqi Peng: Wuhan University
Zihong Xu: Wuhan University
Wen Zhang: Wuhan University
Yuxiang Qiu: Chinese Academy of Sciences
Yang Wu: Chinese Academy of Sciences
Chaohui Ye: Chinese Academy of Sciences
Kunzhang Lin: Chinese Academy of Sciences
Fuqiang Xu: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Viral tracers that enable efficient retrograde labeling of projection neurons are powerful vehicles for structural and functional dissections of the neural circuit and for the treatment of brain diseases. Currently, some recombinant adeno-associated viruses (rAAVs) based on capsid engineering are widely used for retrograde tracing, but display undesirable brain area selectivity due to inefficient retrograde transduction in certain neural connections. Here we developed an easily editable toolkit to produce high titer AAV11 and demonstrated that it exhibits potent and stringent retrograde labeling of projection neurons in adult male wild-type or Cre transgenic mice. AAV11 can function as a powerful retrograde viral tracer complementary to AAV2-retro in multiple neural connections. In combination with fiber photometry, AAV11 can be used to monitor neuronal activities in the functional network by retrograde delivering calcium-sensitive indicator under the control of a neuron-specific promoter or the Cre-lox system. Furthermore, we showed that GfaABC1D promoter embedding AAV11 is superior to AAV8 and AAV5 in astrocytic tropism in vivo, combined with bidirectional multi-vector axoastrocytic labeling, AAV11 can be used to study neuron-astrocyte connection. Finally, we showed that AAV11 allows for analyzing circuit connectivity difference in the brains of the Alzheimer’s disease and control mice. These properties make AAV11 a promising tool for mapping and manipulating neural circuits and for gene therapy of some neurological and neurodegenerative disorders.

Date: 2023
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DOI: 10.1038/s41467-023-39554-7

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