Reduction of depression-like behavior in rat model induced by ShRNA targeting norepinephrine transporter in locus coeruleus

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Abstract

Depression may be associated with reduced monoamine neurotransmission, particularly serotonin and norepinephrine (NE). Reuptake of NE by the norepinephrine transporter (NET) is the primary mechanism by which many of the antidepressants are high-affinity substrates for NET. This study aimed to examine the effect of lentivirus-mediated shRNA targeting NET in locus coeruleus (LC) on depression-like behaviors of rats. We randomly assigned 60 male Wistar rats to 6 experimental groups: (1) Control group: without chronic unpredictable mild stress (CUMS) and without NET-shRNA treatment; (2) shRNA group: without CUMS + NET-shRNA; (3) CUMS group: 3-week CUMS without NET-shRNA; (4) CUMS + nonsense shRNA group; (5) CUMS + amygdala (Amy)-shRNA group; (6) CUMS+ locus coeruleus (LC)-shRNA group. First, recombinant lentiviral vector expressing shRNA (ShRNA-629, ShRNA-330, ShRNA-1222, ShRNA-1146 or ShRNA- negative control) against NET were produced, and their efficiency in knocking down of NET in PC12 cells were assessed by Q-PCR and western blot analysis. Second, shRNA was injected into the rat LC bilaterally to investigate whether it could prevent the depressive-like behavior induced by 3-week CUMS. Third, we tested the depressive-like behavior of the rats in the forced swimming test, the open field test, the sucrose preference test, as well as the body weight gain at the end of the seventh week. Finally, the protein expressions of NET was measured by western blot and the NE levels were measured by high performance liquid chromatography. Q-PCR and western blot showed that the ShRNA-1146 had the best interference efficiency targeting on NET in PC12 cells ( p < 0.01). Compared to the depression model group, the immobility time in the forced swimming test was significantly reduced ( p < 0.01), but the sucrose preference and the total scores in the open field test were significantly increased (all p < 0.01) in the group treated with shRNA in LC. Furthermore, compared with the depression model group, NET levels were significantly decreased ( p < 0.01), but NE levels were significantly increased in the group treated with shRNA in LC ( p < 0.05). Our findings suggest that Lentivirus-mediated shRNA targeting NET in LC downregulated NET both in vitro and in vivo, resulting in a significant decrease in depressive-like behavior of rats.

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Author and article information

Contributors

Xiangdong Du: xiangdong-du@163.com

Xiang Yang Zhang:

ORCID: http://orcid.org/0000-0003-3326-382X

zhangxy@psych.ac.cn

Journal

Journal ID (nlm-ta): Transl Psychiatry

Journal ID (iso-abbrev): Transl Psychiatry

Title: Translational Psychiatry

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2158-3188

Publication date (Electronic): 4 May 2020

Publication date PMC-release: 4 May 2020

Publication date Collection: 2020

Volume: 10

Electronic Location Identifier: 130

Affiliations

[1 ]ISNI 0000 0001 0198 0694, GRID grid.263761.7, Suzhou Psychiatric Hospital, , The Affiliated Guangji Hospital of Soochow University, ; Suzhou, China

[2 ]ISNI 0000 0001 0807 1581, GRID grid.13291.38, Department of Psychiatry and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, , Sichuan University, ; Chengdu, China

[3 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Department of Psychiatry and Behavioral Sciences, , Baylor College of Medicine, ; Houston, TX USA

[4 ]ISNI 0000000119573309, GRID grid.9227.e, CAS Key Laboratory of Mental Health, Institute of Psychology, , Chinese Academy of Sciences, ; Beijing, China

[5 ]ISNI 0000 0004 1797 8419, GRID grid.410726.6, Department of Psychology, , University of Chinese Academy of Sciences, ; Beijing, China

Author information

Xiang Yang Zhang http://orcid.org/0000-0003-3326-382X

Article

Publisher ID: 808

DOI: 10.1038/s41398-020-0808-8

PMC ID: 7198598

PubMed ID: 32366842

SO-VID: 382c1a86-5e26-487c-a454-ac25d9508a98

License:

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