Selective targeting of striatal parvalbumin-expressing interneurons for transgene delivery

Abstract

PV^Cre mice--> combined with AAV-FLEX vectors allowed efficient and specific targeting of PV⁺ interneurons in the striatum. However, diffusion of viral particles to the globus pallidus caused massive transduction of PV⁺ projection neurons and subsequent anterograde transport of the transgene product to the subthalamic nucleus and the substantia nigra pars reticulata. Different AAV serotypes (1 and 9) and promoters (CBA and human synapsin) were evaluated. The combination of AAV1, a moderate expression level (human synapsin promoter) and a precise adjustment of the stereotaxic coordinates in the anterior and dorsolateral part of the striatum were necessary to avoid transduction of PV⁺ GP projection neurons. Even in the absence of direct transduction due to diffusion of viral particles, GP PV⁺ projection neurons could be retrogradely transduced via their terminals present in the dorsal striatum. However, in the absence of diffusion, GP-Str PV⁺ projection neurons were poorly or not transduced suggesting that retrograde transduction did not significantly impair the selective targeting of striatal PV⁺ neurons. Finally, a prominent reduction of the number of striatal PV⁺ interneurons (about 50 %) was evidenced in the presence of the Cre recombinase suggesting that functional effects of AAV-mediated transgene expression in PV⁺ striatal interneurons in PV^Cre mice should be analyzed with caution.

Keywords: AAV-FLEX vectors; Fast-spiking interneurons; PV(Cre) mice; Parvalbumin; Striatum.