Transgenic Cre-recombinase expressing mouse lines are widely used to express fluorescent proteins and opto-/chemogenetic actuators, making them a cornerstone of modern neuroscience. The investigation of interneurons in particular has benefitted from the ability to genetically target specific cell types. However, the specificity of some Cre driver lines has been called into question. Here, we show that nonspecific expression in a subset of hippocampal neurons can have substantial nonspecific functional effects in a somatostatin-Cre (SST-Cre) mouse line. Nonspecific targeting of CA3 pyramidal cells caused large optogenetically evoked excitatory currents in remote brain regions. Similar, but less severe patterns of nonspecific expression were observed in a widely used SST-IRES-Cre line, when crossed with a reporter mouse line. Viral transduction on the other hand yielded more specific expression but still resulted in nonspecific expression in a minority of pyramidal layer cells. These results suggest that a careful analysis of specificity is mandatory before the use of Cre driver lines for opto- or chemogenetic manipulation approaches.

表达Cre重组酶的转基因小鼠系被广泛用于表达荧光蛋白和光/化学致动器，使其成为现代神经科学的基石。中间神经元的研究特别受益于基因靶向特定细胞类型的能力。但是，某些Cre驱动程序线的特殊性已受到质疑。在这里，我们显示出海马神经元子集中的非特异性表达在生长抑素-Cre（SST-Cre）小鼠系中可能具有实质性的非特异性功能作用。CA3锥体细胞的非特异性靶向在遥远的大脑区域引起大量的光遗传学诱发的兴奋性电流。当与报告基因小鼠品系杂交时，在广泛使用的SST-IRES-Cre品系中观察到相似但较不严重的非特异性表达模式。另一方面，病毒转导产生更特异性的表达，但仍在少数锥体细胞中产生非特异性表达。这些结果表明，在将Cre驱动系用于光或化学遗传学操作方法之前，必须对特异性进行仔细的分析。