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Pro-BDNF Knockout Causes Abnormal Motor Behaviours and Early Death in Mice

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2020

Neuroscience. 2020 May 13;438:145-157. doi: 10.1016/j.neuroscience.2020.05.007.

Pro-BDNF Knockout Causes Abnormal Motor Behaviours and Early Death in Mice

H Li;LY L;Y Zhang;Y Lim;M Rahman;A Beck;M Al-Hawwas;S Feng;L Bobrovskaya;XF Zhou

School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA 5001, Australia. Department of Orthopaedics, Tianjin Medical University General Hospital, Tianjin 300052, China. Centre for Cancer Biology, University of South Australia, Adelaide, SA 5001, Australia.

Service type: Knock-in mice

Abstract

Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family, best characterized for its survival and differentiative effects in the central nervous system. Pro-BDNF, known as the precursor of BDNF, is believed to have opposite functions to mature BDNF (mBDNF). The opposing effects of Pro-BDNF and mBDNF have led researchers to propose a 'yin' (Pro-BDNF) and 'yang' (mBDNF) model of which, the specific mechanism of its opposing functions is unclear and requires further investigation. In order to elucidate pro-BDNF's explicit role, we established a pro-BDNF knockout (KO) mouse model. This BDNF pro-domain KO mouse model showed significant weight loss, impaired righting reflex, abnormal motor behaviours and short lifespan (less than 22 days), mimicking a Huntington's disease (HD)-like phenotype. ELISA results showed BDNF pro-domain KO not only blocked pro-BDNF, but also significantly affected the level of mBDNF. Abnormal morphologic changes were found in the dentate gyrus (DG) of the hippocampus in pro-BDNF KO mice, and western blot confirmed significant cell apoptosis in pro-BDNF KO mice brains. Furthermore, the expression of glutamic acid decarboxylase 65/67 (GAD65/67) was significantly reduced in pro-BDNF KO mice, indicating impaired inhibitory neurotransmission. Heterozygous (Het) mice showed impaired learning and memory capability and depressive-like behaviours, compared with wild type (WT) mice. Overall, these results support that pro-domain of BDNF is an indispensable part of the BDNF gene; without the proper formation of pro-BDNF, mBDNF cannot be produced successfully and function correctly on its own. Our study also supports the BDNF hypothesis in the pathogenesis of HD.

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