Conditional Genome Editing in the Mammalian Brain Using CRISPR-Cas9
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INSIGHT
Conditional Genome Editing in the Mammalian Brain Using CRISPR-Cas9 Haojie Sun1,2
•
Jie Zheng3 • Ming Yi1
•
You Wan1,2
Received: 18 April 2020 / Accepted: 3 June 2020 Ó Shanghai Institutes for Biological Sciences, CAS 2020
Neuronal ensembles with distinct morphological, biochemical, and functional identities are organized into complex circuits in the mammalian brain, and malfunction of specific neuronal types in different networks contributes to diverse pathological symptoms. Taking memory as an example, specific memories are held in a subset of neurons, referred to as engram cells. Conditional genome manipulation in the heterogeneous brain would provide a powerful tool for investigating the encoding and storage of specific memories. Recently, Sun et al. [1] developed a clustered regularly interspaced short palindromic repeats (CRISPR)associated endonuclease Cas9 system for precise genomic perturbations in specific neuronal subpopulations with high temporal and spatial specificity, which can be widely applied in revealing brain functions including memory.
Substrate for Memory Storage Memory refers to the storage of learned information in the nervous system; it is vital to adaptive behavior in mammals. Pharmacological research has largely relied on the impairment of a broad brain region, rather than a
& You Wan [email protected] 1
Neuroscience Research Institute, Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100083, China
2
Key Laboratory for Neuroscience, Ministry of Education/ National Health Commission of China, Peking University, Beijing 100083, China
3
Department of Pathophysiology, Huazhong University of Science and Technology, Wuhan 430030, China
specific subset of neurons relevant to a given memory. It is now known that only a small number of neurons, the engram cells, is necessary to encode a memory. Selective ablation or inhibition of engram cells erases the memory response, while direct activation can induce the associated behavioral output [2]. Engram cells were first identified by the combination of immediate early gene (IEG) labeling with a doxycycline-inducible system [2]. The expression of IEGs, including arc and c-fos, are frequently used as biomarkers of neuronal excitation [3, 4]. During a given learning experience, the promoter of an IEG can be coopted to label activated neurons with exogenous protein, such as fluorescent protein, b-galactosidase, or an optogenetic component [2, 5]. For decades, memory encoding has been hypothesized to involve structural changes at the synaptic junctions of neuronal ensembles, and strengthening of synaptic connections of existing neurons might underlie memory storage [6]. However, recent results have demonstrated that memory information is still retained in engram cells even in the absence of engram cell-specific reinforcement of synaptic strength, showing a stark dissociation between memory content and synaptic plasticity [7]. It was recently speculated th
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