Banks Emmie, Gutekunst Claire-Anne, Vargish Geoffrey A, Eaton Anna, Pelkey Kenneth A, McBain Chris J, Zheng James Q, Oláh Viktor Janos, Rowan Matthew Jm
bioRxiv. 2023 May 11:2023.02.03.527045. doi: 10.1101/2023.02.03.527045.
The mammalian brain contains the most diverse array of cell types of any organ, including dozens of neuronal subtypes with distinct anatomical and functional characteristics. The brain leverages these neuron-type-specializations to perform diverse circuit operations and thus execute different behaviors properly. Through the use of Cre lines, access to specific neuron types has steadily improved over past decades. Despite their extraordinary utility, development and cross-breeding of Cre lines is time-consuming and expensive, presenting a significant barrier to entry for many investigators. Furthermore, cell-based therapeutics developed in Cre mice are not clinically translatable. Recently, several AAV vectors utilizing neuron-type-specific regulatory transcriptional sequences (enhancer-AAVs) were developed which overcome these limitations. Using a publicly available RNAseq dataset, we evaluated the potential of several candidate enhancers for neuron-type-specific targeting in the hippocampus. Here we identified a promising enhancer-AAV for targeting dentate granule cells and validated its selectivity in wild-type adult mice.
哺乳动物的大脑包含了所有器官中最为多样的细胞类型，其中包括几十种具有独特解剖学和功能特征的神经元亚型。大脑利用这些神经元类型特化来执行各种神经回路操作，从而正确地执行不同行为。在过去几十年里，通过使用Cre品系，对特定神经元类型的研究条件一直在稳步改善。尽管它们具有非凡的实用性，但Cre品系的开发和杂交既耗时又昂贵，这对许多研究人员来说是一个重大的进入障碍。此外，在Cre小鼠中开发的基于细胞的疗法无法进行临床转化。最近，人们开发了几种利用神经元类型特异性调控转录序列的腺相关病毒载体（增强子-AAV），克服了这些限制。利用一个公开可用的RNA测序数据集，我们评估了几种候选增强子在海马体中进行神经元类型特异性靶向的潜力。在这里，我们鉴定出一种有前景的用于靶向齿状颗粒细胞的增强子-AAV，并在野生型成年小鼠中验证了其选择性。
