PMID- 29989126 OWN - NLM STAT- MEDLINE DCOM- 20190816 LR - 20190816 IS - 1756-591X (Electronic) IS - 1756-5901 (Linking) VI - 10 IP - 7 DP - 2018 Jul 18 TI - Conditioned medium from overly excitatory primary astrocytes induced by La(3+) increases apoptosis in primary neurons via upregulating the expression of NMDA receptors. PG - 1016-1028 LID - 10.1039/c8mt00056e [doi] AB - Lanthanum (La) can accumulate in the brain and impair learning and memory. However, the underlying mechanism of La-induced neurotoxicity has remained elusive. Under physiological conditions, it has been reported that moderately excitatory astrocytes play an important role in the regulation of neuronal signals and synaptic plasticity. However, under pathological conditions, overly excitatory astrocytes can release excess excitatory transmitters, such as glutamate (Glu) and d-serine, and induce the over-activation of NMDA receptors (NMDAR) in neurons, ultimately leading to neuronal excitotoxicity. To date, limited work has been performed with respect to whether La can induce neuronal excitotoxicity by inducing astrocytes to become overexcited. In this study, in vitro models of primary culture rat cortical astrocytes and neurons were established. First, the astrocytes were treated with 0.125 mM, 0.25 mM and 0.5 mM lanthanum chloride (LaCl3) for 24 h, and the supernatants were collected as a conditioned medium (CM) which is denoted as CM (La3+); then, the neurons were treated with CM (La3+) for 48 h. The results illustrate that LaCl3 treatment significantly upregulated the mRNA and protein expression levels of metabotropic glutamate receptor 5 (mGLUR5), phospholipase C (PLC), connexin 43 (Cx43) and Cx30, increased the concentrations of inositol trisphosphate (IP3) and [Ca2+]i, and promoted the synthesis and release of Glu and d-serine in astrocytes. Moreover, the CM (La3+) could increase the mRNA and protein expression levels of NMDAR subunits (NR1, NR2A, NR2B), the concentration of [Ca2+]i and the rate of apoptosis in neurons. Furthermore, after removal of La, CM (La-free) had a similar effect on neurons which could be antagonized by MK-801, DCKA and DAAO. These results suggest that the neuron apoptosis induced by La is closely related to the excessive release of Glu and d-serine from overly excitatory astrocytes. FAU - Sun, Yaling AU - Sun Y AD - Department of Toxicology, School of Public Health, China Medical University, No. 77 Puhe road, Shenyang North New Area, Shenyang 110122, Liaoning Province, People's Republic of China. YalingSun_C1988@163.com ycai@cmu.edu.cn. FAU - Yang, Jinghua AU - Yang J FAU - Hu, Xiaoyu AU - Hu X FAU - Gao, Xiang AU - Gao X FAU - Li, Yingqi AU - Li Y FAU - Yu, Miao AU - Yu M FAU - Liu, Shiyu AU - Liu S FAU - Lu, Yanxin AU - Lu Y FAU - Wang, Jing AU - Wang J FAU - Huang, Liling AU - Huang L FAU - Lu, Xiaobo AU - Lu X FAU - Jin, Cuihong AU - Jin C FAU - Wu, Shengwen AU - Wu S FAU - Cai, Yuan AU - Cai Y LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Metallomics JT - Metallomics : integrated biometal science JID - 101478346 RN - 0 (Culture Media, Conditioned) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 6I3K30563S (Lanthanum) MH - Animals MH - Animals, Newborn MH - *Apoptosis MH - Astrocytes/cytology/*metabolism MH - Cells, Cultured MH - Culture Media, Conditioned/*pharmacology MH - *Gene Expression Regulation MH - Lanthanum/*pharmacology MH - Neuronal Plasticity MH - Neurons/drug effects/metabolism/*pathology MH - Rats MH - Rats, Wistar MH - Receptors, N-Methyl-D-Aspartate/genetics/*metabolism MH - Up-Regulation EDAT- 2018/07/11 06:00 MHDA- 2019/08/17 06:00 CRDT- 2018/07/11 06:00 PHST- 2018/07/11 06:00 [pubmed] PHST- 2019/08/17 06:00 [medline] PHST- 2018/07/11 06:00 [entrez] AID - 10.1039/c8mt00056e [doi] PST - ppublish SO - Metallomics. 2018 Jul 18;10(7):1016-1028. doi: 10.1039/c8mt00056e.