Lentiviral-Mediated Overexpression of the 18 kDa Translocator Protein (TSPO) in the Hippocampal Dentate Gyrus Ameliorates LPS-Induced Cognitive Impairment in Mice.

Wei Wang,Lei Li,Qiang Fu,Liming Zhang,Rui Xue,Weixing Zhao,Weidong Mi,Yunfeng Li,Xiaoying Zhang

doi:10.3389/fphar.2016.00384

Abstract

The 18 kDa translocator protein (TSPO) is involved in the immune/inflammatory response. However, the exact role that TSPO plays in neuroinflammation-induced cognitive impairment is still elusive. The purpose of our present study was to investigate the effects of lentiviral-mediated hippocampal overexpression of the TSPO in a mouse model of LPS-induced cognitive impairment. We established a mouse cognitive impairment model using systematic daily administration of lipopolysaccharide (LPS) (0.5 mg/kg). Microinjection of the dentate gyrus of the mouse with lentiviral vectors, which contained a cDNA targeting TSPO (Lv-TSPO), resulted in a significant increase in TSPO expression and allopregnanolone production. Mice treated with LPS showed cognitive deficits in the novel object recognition test and the Morris water maze test that could be ameliorated by TSPO overexpression. In addition, TSPO overexpression reversed LPS-induced microglial activation and accumulation of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Moreover, TSPO overexpression attenuated the LPS-induced impairment of hippocampal neurogenesis. Our results suggest that local overexpression of TSPO in the hippocampal dentate gyrus alleviated LPS-induced cognitive deficits, and its effects might be mediated by the attenuation of inflammatory cytokines, inhibition of microglial activation, and promotion of neurogenesis.

Highlights

Cognitive impairment, a common and serious symptom, deeply influences people’s quality of life worldwide
The present study demonstrated that overexpression of translocator protein (TSPO) in the hippocampal dentate gyrus significantly suppressed the cognitive impairment induced by LPS in mice and that this effect might be mediated by the attenuation of inflammatory cytokines, inhibition of microglial activation, and promotion of neurogenesis
Numerous TSPO ligands (XBD173, vinpocetine, RO5-4864) could attenuate microglial activation and the accumulation of pro-inflammatory cytokines in vitro and in vivo (Zhao et al, 2011; Bae et al, 2014; Karlstetter et al, 2014). Consistent with these findings, we demonstrated that LPS increased the production of IL-1β, IL-6 and TNF-α, which was reversed by TSPO overexpression and is consistent with behavioral tests

Summary

Introduction

A common and serious symptom, deeply influences people’s quality of life worldwide. TSPO ligands have been developed as potential molecular markers to detect neuroinflammation and have been applied in the assessment of neuroinflammation in patients with several neuropathological conditions that are accompanied by cognitive impairment (Batarseh and Papadopoulos, 2010; Colasanti et al, 2014; Rissanen et al, 2014; Suridjan et al, 2015; Zurcher et al, 2015; Wang et al, 2016) These interesting data gave reason to hypothesize that downregulation of TSPO in the brain could be a risk factor for the etiology of neuroinflammatory cognitive impairment, and increased TSPO might be a novel pharmacological treatment strategy for cognitive impairment

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