Peripheral ProBDNF Delivered by an AAV Vector to the Muscle Triggers Depression-Like Behaviours in Mice
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ORIGINAL ARTICLE
Peripheral ProBDNF Delivered by an AAV Vector to the Muscle Triggers Depression-Like Behaviours in Mice L. Y. Lin 1 & S. Kelliny 1 & L. C. Liu 1 & M. Al-Hawwas 1 & X. F. Zhou 1 & L. Bobrovskaya 1 Received: 27 April 2020 / Revised: 22 June 2020 / Accepted: 6 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Major depression is a leading cause of morbidity and disease burden in modern society. Current drug treatment is only effective in a fraction of patients as underlying mechanisms of depression are not fully understood. ProBDNF, a precursor of brain-derived neurotrophic factor (BDNF), and its receptor p75NTR are highly upregulated in patients with major depression and in animal models of depression induced by chronic stress. Here, we hypothesise that proBDNF may be a pathogenic factor triggering depression. C57BL/6 mice were injected in the bilateral gluteus maximus muscle with AAV-proBDNF or AAV-EGFP. Four weeks after the injection, AAV-proBDNF injected animals developed depression-like behaviours, which were evident for 4– 8 weeks and then returned to the control level after 12 weeks. In the second experiment, mice were divided into three groups; one group was treated with sheep anti-proBDNF antibody after AAV-proBDNF injection whereas the other two groups received PBS injection after the AAV-proBDNF or AAV-EGFP delivery. The group that was injected with AAV-proBDNF showed a timedependent increase in immobility time in the tail suspension test and forced swim test, reduced sucrose consumption and decreased grooming time after sucrose spraying. Treatment with sheep anti-proBDNF antibody alleviated the depressive-like symptoms. Peripheral AAV-proBDNF delivery also resulted in a reduction of density and length of dendritic spines in the dentate gyrus and amygdala. Thus, we conclude that peripheral proBDNF is a primary pathogenic factor triggering depression-like behavioural changes in mice likely by reducing dendritic spine plasticity. Keywords Depression . ProBDNF . Behavioural tests . Golgi stain . AAV . Anti-proBDNF antibody
Introduction Depression is a leading cause of disability and heads the list of brain diseases in terms of prevalence and economic burden (Malhi and Mann 2018; Johnston et al. 2019). However, the pathogenesis and mechanisms underlying its development are not well established (Kennis et al. 2020; Pitsillou et al. 2020). Although there are over 20 drugs partially efficacious for treating mood disorder in a subpopulation of sufferers, the high relapse rates and the fact that some patients are refractory to any therapy call for intensive investigation to solve this serious problem in human health (Johnston et al. 2019).
* L. Bobrovskaya [email protected] 1
Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia
The BDNF (brain-derived neurotrophic factor) hypothesis was proposed 25 years ago based on the evidence that BDNF is reduced in the brains
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