Pro-BDNF Knockout Causes Abnormal Motor Behaviours and Early Death in Mice. (1st July 2020)

• Record Type: Journal Article
• Authors: Li, Hua; Lin, Li-Ying; Zhang, Yan; Lim, Yoon; Rahman, Mehreen; Beck, Andrew; Al-Hawwas, Mohammed; Feng, Shiqing; Bobrovskaya, Larisa; Zhou, Xin-Fu
• Is Part Of: Neuroscience. Volume 438(2020)
• Page Start: 145
• Page End: 157
• Publication Date: 2020-07-01
• Subjects: BDNF brain derived neurotrophic factor -- DG dentate gyrus -- EDTA ethylenediaminetetraacetic acid -- ELISA enzyme-linked immunosorbent assay -- HAP1 huntingtin-associated protein-1 -- HD Huntington's disease -- LTD long term depression -- mBDNF mature BDNF -- MMP metalloproteinase -- PFA paraformaldehyde; BDNF -- pro-BDNF -- knockout -- apoptosis -- GAD65/67 -- Huntington disease; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2020.05.007
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Pro-BDNF KO mouse model established by deleting BDNF pro-domain. BDNF pro-domain KO not only blocks the expression of pro-BDNF but also mBDNF. BDNF pro-domain KO leads to weight loss, abnormal motor behaviours and short lifespan in mice. BDNF pro-domain KO causes apoptotic change in mouse brain. GAD65/67 expression is significantly reduced in pro-BDNF KO mouse brain. 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.