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Peripheral ProBDNF Delivered by an AAV Vector to the Muscle Triggers Depression-Like Behaviours in Mice

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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 time-dependent 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.

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Acknowledgements

This work was supported by UniSA Postgraduate Scholarship to Liy.L., NHMRC Fellowship grant to X.F.Z. and a collaboration grant from Shanghai Yile Biotech. The authors wish to thank Moses Chao from New York University for the gift of p75NTR antibodies.

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Authors and Affiliations

  1. Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia

    L. Y. Lin, S. Kelliny, L. C. Liu, M. Al-Hawwas, X. F. Zhou & L. Bobrovskaya

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  1. L. Y. Lin
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  2. S. Kelliny
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  3. L. C. Liu
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  4. M. Al-Hawwas
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  5. X. F. Zhou
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Contributions

L.B. and X.F.Z. contributed to the study conception and design. Material preparation, data collection and analysis were performed by Liy.L., S.K., Lin.L. and M.A.-H. The first draft of the manuscript was written by Liy.L. and all authors provided their comments. All authors read and approved the final manuscript.

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Correspondence to L. Bobrovskaya.

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Lin, L.Y., Kelliny, S., Liu, L.C. et al. Peripheral ProBDNF Delivered by an AAV Vector to the Muscle Triggers Depression-Like Behaviours in Mice. Neurotox Res 38, 626–639 (2020). https://doi.org/10.1007/s12640-020-00256-3

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