Retrograde Transgene Expression via Neuron-Specific Lentiviral Vector Depends on Both Species and Input Projections.

Yukiko Otsuka,Shigeki Kato,Katsuki Nakamura,Maki Fujiwara,Miki Miwa,Soshi Tanabe,Masahiko Takada,Kazuto Kobayashi,Ken-Ichi Inoue,Shiori Uezono,Hitomi Tsuge

doi:10.3390/v13071387

Yukiko Otsuka, Shigeki Kato + Show 9 more

Open Access

https://doi.org/10.3390/v13071387

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Abstract

For achieving retrograde gene transfer, we have so far developed two types of lentiviral vectors pseudotyped with fusion envelope glycoprotein, termed HiRet vector and NeuRet vector, consisting of distinct combinations of rabies virus and vesicular stomatitis virus glycoproteins. In the present study, we compared the patterns of retrograde transgene expression for the HiRet vs. NeuRet vectors by testing the cortical input system. These vectors were injected into the motor cortex in rats, marmosets, and macaques, and the distributions of retrograde labels were investigated in the cortex and thalamus. Our histological analysis revealed that the NeuRet vector generally exhibits a higher efficiency of retrograde gene transfer than the HiRet vector, though its capacity of retrograde transgene expression in the macaque brain is unexpectedly low, especially in terms of the intracortical connections, as compared to the rat and marmoset brains. It was also demonstrated that the NeuRet but not the HiRet vector displays sufficiently high neuron specificity and causes no marked inflammatory/immune responses at the vector injection sites in the primate (marmoset and macaque) brains. The present results indicate that the retrograde transgene efficiency of the NeuRet vector varies depending not only on the species but also on the input projections.

Highlights

Lentiviral vectors based on HIV-1 have been developed for gene transfer experiments in the brain [1,2,3]
In the present series of experiments, the same three vectors were utilized for investigating the patterns of retrograde transgene expression in the cortical input system
We injected these vectors into the medial part of the frontal motor cortex, corresponding to the M2 in rats, area 6m (A6m) in marmosets, and supplementary motor area (SMA) in macaques

Summary

Introduction

Lentiviral vectors based on HIV (human immunodeficiency virus)-1 have been developed for gene transfer experiments in the brain [1,2,3]. A viral vector that allows gene transfer through retrograde axonal transport infects axon terminals of neurons at its injection site and expresses the transgene at cell bodies in a region projecting to the injection site. Since such a retrograde infection-type vector provides a powerful tool for pathway-selective manipulation and monitoring of neuronal activity, recent attention has been paid to pseudotyped lentiviral vectors [4,5,6,7,8,9,10,11,12,13]. Both of these vectors successfully achieve highly efficient retrograde gene transfer

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