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Type: Journal article
Title: Pro-BDNF knockout causes abnormal motor behaviours and early death in mice
Author: Li, H.
Lin, L.Y.
Zhang, Y.
Lim, Y.
Rahman, M.
Beck, A.
Al-Hawwas, M.
Feng, S.
Bobrovskaya, L.
Zhou, X.F.
Citation: Neuroscience, 2020; 438:145-157
Publisher: Elsevier
Issue Date: 2020
ISSN: 0306-4522
Statement of
Hua Li, Li-Ying Lin, Yan Zhang, Yoon Lim, Mehreen Rahman, Andrew Beck, Mohammed Al-Hawwas, Shiqing Feng, Larisa Bobrovskaya and Xin-Fu Zhou
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.
Keywords: BDNF; pro-BDNF; knockout; apoptosis; GAD65/67; Huntington disease
Rights: © 2020 Published by Elsevier Ltd on behalf of IBRO.
DOI: 10.1016/j.neuroscience.2020.05.007
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