Laboratory of Cellular Neurobiology of Learning, Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485 Moscow, Russia.
Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia.
Cells. 2021 Jun 25;10(7):1600. doi: 10.3390/cells10071600.
In the current review, we aim to discuss the principles and the perspectives of using the genetic constructs based on AAV vectors to regulate astrocytes' activity. Practical applications of optogenetic approaches utilizing different genetically encoded opsins to control astroglia activity were evaluated. The diversity of astrocytic cell-types complicates the rational design of an ideal viral vector for particular experimental goals. Therefore, efficient and sufficient targeting of astrocytes is a multiparametric process that requires a combination of specific AAV serotypes naturally predisposed to transduce astroglia with astrocyte-specific promoters in the AAV cassette. Inadequate combinations may result in off-target neuronal transduction to different degrees. Potentially, these constraints may be bypassed with the latest strategies of generating novel synthetic AAV serotypes with specified properties by rational engineering of AAV capsids or using directed evolution approach by searching within a more specific promoter or its replacement with the unique enhancer sequences characterized using modern molecular techniques (ChIP-seq, scATAC-seq, snATAC-seq) to drive the selective transgene expression in the target population of cells or desired brain regions. Realizing these strategies to restrict expression and to efficiently target astrocytic populations in specific brain regions or across the brain has great potential to enable future studies.
在本次综述中，我们旨在讨论使用基于 AAV 载体的基因构建物来调节星形胶质细胞活性的原则和观点。评估了利用不同遗传编码光敏感蛋白来控制星形胶质细胞活性的光遗传学方法的实际应用。星形胶质细胞的细胞类型多样性使得为特定实验目标设计理想的病毒载体变得复杂。因此，高效和充分的星形胶质细胞靶向是一个多参数的过程，需要将天然倾向于转导星形胶质细胞的特定 AAV 血清型与 AAV 盒中的星形胶质细胞特异性启动子相结合。不适当的组合可能导致不同程度的非靶向神经元转导。潜在地，可以通过合理的 AAV 衣壳工程或通过在更特定的启动子内搜索或用使用现代分子技术（ChIP-seq、scATAC-seq、snATAC-seq）鉴定的独特增强子序列替换来生成具有特定特性的新型合成 AAV 血清型的最新策略来绕过这些限制，以在目标细胞群或所需的大脑区域中驱动选择性转基因表达。实现这些策略以限制表达并有效地靶向特定脑区或整个脑区的星形胶质细胞群体具有很大的潜力，可以为未来的研究提供支持。
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