Journal
NATURE NEUROSCIENCE
Volume 21, Issue 3, Pages 447-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41593-018-0077-5
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Funding
- National Key R&D Program of China [2016YFA0101900, 2016YFC0903301]
- National Natural Science Foundation of China [31771482, 31471020, 31161120358]
- National Basic Research Program of China [2015CB910603]
- Beijing Municipal Science & Technology Commission [Z161100002616010]
- Key Research Program of the CAS [KJZD-EW-L14]
- Open Project of Key Laboratory of Genomic and Precision Medicine of the CAS
- Open Project of State Key Laboratory of Membrane Biology of China
- JPB Foundation
- Leona M. and Harry B. Helmsley Charitable Trust
- NIH [R01MH114030, U19MH106434]
- G. Harold & Leila Y. Mathers Foundation
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CRISPR-Cas9 has been demonstrated to delete genes in postmitotic neurons. Compared to the establishment of proliferative cell lines or animal strains, it is more challenging to acquire a highly homogeneous consequence of gene editing in a stable neural network. Here we show that dCas9-based CRISPR interference (CRISPRi) can efficiently silence genes in neurons. Using a pseudotarget fishing strategy, we demonstrate that CRISPRi shows superior targeting specificity without detectable off-target activity. Furthermore, CRISPRi can achieve multiplex inactivation of genes fundamental for neurotransmitter release with high efficiency. By developing conditional CRISPRi tools targeting synaptotagmin I (Syt1), we modified the excitatory to inhibitory balance in the dentate gyrus of the mouse hippocampus and found that the dentate gyrus has distinct regulatory roles in learning and affective processes in mice. We therefore recommend CRISPRi as a useful tool for more rapid investigation of gene function in the mammalian brain.
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