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Front Neural Circuits . 2020 Apr 27

Nonspecific Expression in Limited Excitatory Cell Populations in Interneuron-Targeting Cre-driver Lines Can Have Large Functional Effects

Frederic Brosseron, Carl-Christian Kolbe, Francesco Santarelli, Stephanie Carvalho, Anna Antonell, Sergio Castro-Gomez, Pawel Tacik, Aishwarya Alex Namasivayam, Graziella Mangone, Reinhard Schneider, Eicke Latz, Ullrich Wüllner, Per Svenningsson, Raquel Sánchez-Valle, José Luis Molinuevo, Jean-Christophe Corvol, Michael T Heneka, AETIONOMY study group, Daniel Müller-Komorowska, Thoralf Opitz, Shehabeldin Elzoheiry, Michaela Schweizer, Eleonora Ambrad Giovannetti, Heinz Beck

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.

PMID: 32395103