Key Laboratory of Cell Biology of Ministry of Public Health of China, College of Basic Medical Sciences, China Medical University, Shenyang 110001, People's Republic of China.
Hippocampus. 2011 May;21(5):495-501. doi: 10.1002/hipo.20767.
It is well-known that zinc deficiency leads to neuronal death in the brain. Here we tested the hypothesis that changes in the TrkB signaling pathway are involved in hippocampal neuronal apoptosis of suckling offspring with maternal zinc deficiency. Postpartum mice were fed a zinc-deficient (0.85 ppm) diet and their offspring were used as a lactational zinc deficiency mouse model. At P7, P14, and P21, changes in hippocampal neuronal apoptosis were assessed by Nissl and TUNEL staining. BDNF levels and TrkB neurotrophic signaling were examined using immunoblotting assay. Lactational zinc deficiency resulted in lower levels of p-TrkB and p-ERK, and higher levels of Bax/Bcl-2 and caspase-3 in the hippocampus, suggesting that zinc deficiency-induced low levels of TrkB phosphorylation would abrogate the downstream ERK signaling pathway, leading to hippocampal neuronal apoptosis. Most interestingly, our data showed that the activity of Src, a key molecule for zinc-induced TrkB activation through the BDNF-independent pathway, was inhibited significantly, and the expression levels of BDNF were significantly increased in the hippocampus of suckling mice. The present data indicate that zinc depletion-induced hippocampal neuronal apoptosis is likely through modulation of the TrkB neurotrophic signaling pathway by a BDNF-independent and Src-dependent mechanism, whereas higher expression of BDNF is considered as a protective response, which cannot fully compensate for the injury caused by maternal zinc deficiency.
众所周知，锌缺乏会导致大脑神经元死亡。在这里，我们检验了这样一个假设，即 TrkB 信号通路的变化参与了母体缺锌的哺乳期后代海马神经元凋亡。产后小鼠喂食缺锌（0.85ppm）饮食，其后代用作哺乳期缺锌小鼠模型。在 P7、P14 和 P21 时，通过尼氏染色和 TUNEL 染色评估海马神经元凋亡的变化。使用免疫印迹检测 BDNF 水平和 TrkB 神经营养信号。哺乳期缺锌导致海马中 p-TrkB 和 p-ERK 水平降低，Bax/Bcl-2 和 caspase-3 水平升高，表明锌缺乏诱导的 TrkB 磷酸化水平降低会阻断下游 ERK 信号通路，导致海马神经元凋亡。最有趣的是，我们的数据表明，Src 的活性（锌通过 BDNF 非依赖性途径激活 TrkB 的关键分子）显著抑制，而 BDNF 的表达水平在哺乳期小鼠的海马中显著增加。目前的数据表明，锌耗竭诱导的海马神经元凋亡可能是通过 BDNF 非依赖性和 Src 依赖性机制调节 TrkB 神经营养信号通路，而 BDNF 的高表达被认为是一种保护反应，不能完全补偿母体缺锌造成的损伤。
