Bilirubin impairs neuritogenesis and synaptogenesis in NSPCs by downregulating NMDAR-CREB-BDNF signaling

作者全名："Zhang, Yan; Li, Siyu; Li, Ling; Huang, Hongmei; Fu, Zhou; Hua, Ziyu"

作者地址："[Zhang, Yan] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Key Lab Child Dev & Disorders, Chongqing Key Lab Child Infect & Immun,Minist Educ, Chongqing, Peoples R China; [Li, Siyu; Li, Ling; Huang, Hongmei; Hua, Ziyu] Chongqing Med Univ, Dept Neonatol, Childrens Hosp, Chongqing 400014, Peoples R China; [Fu, Zhou] Chongqing Med Univ, Childrens Hosp, Dept Resp Dis, Chongqing 400014, Peoples R China"

通信作者："Hua, ZY (通讯作者)，Chongqing Med Univ, Dept Neonatol, Childrens Hosp, Chongqing 400014, Peoples R China.; Fu, Z (通讯作者)，Chongqing Med Univ, Childrens Hosp, Dept Resp Dis, Chongqing 400014, Peoples R China."

来源：IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001141174900001

JCR分区：Q3

影响因子：2.1

年份：2024

卷号：60

期号：2

开始页：161

结束页：171

文献类型：Article

关键词：Bilirubin; NSPCs; Neuritogenesis; Synaptogenesis; CREB

摘要："Neonatal jaundice is one of the most common disorders in the first 2 wk after birth. Unconjugated bilirubin (UCB) is neurotoxic and can cause neurological dysfunction; however, the underlying mechanisms remain unclear. Neurogenesis, neuronal growth, and synaptogenesis are exuberant in the early postnatal stage. In this study, the impact of UCB on neuritogenesis and synaptogenesis in the early postnatal stage was evaluated both in vitro and in vivo. Primary culture neuronal stem and progenitor cells (NSPCs) were treated with UCB during differentiation, and then the neurite length and synapse puncta were measured. In the bilirubin encephalopathy (BE) animal model, DCX+-marked developing neurons were used to detect apical length and dendritic arborization. According to the data, UCB significantly reduced neurite length and synapse density, as well as decreased the apical dendrite length and dendritic arborization. Furthermore, the NMDAR subunit NR2B was downregulated in NSPCs, while pCREB expression in the hippocampus progressively decreased during disease progression in the BE model. Next, we tested the expression of NR2B, pCREB, mBDNF, and p-mTOR in NSPCs in vitro, and found that UCB treatment reduced the expression of these proteins. In summary, this suggests that UCB causes chronic neurological impairment and is related to the inhibition of NMDAR-CREB-BDNF signaling in NSPCs, which is associated with reduced neuritogenesis and synaptogenesis. This finding may inspire the development of novel pharmaceuticals and treatments."

基金机构：National Natural Science Foundation of China

基金资助正文：The authors wish to thank Xiaohui Xu and Xuemei Liao for their generous technical support for laser confocal photography.