Department of Neonatology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi 710061, China.
Shaanxi Province Biomedicine Key Laboratory, College of Life Science, Northwest University, 229 Taibai North Road, Xi'an, Shaanxi 710079, China.
Neuroscience. 2019 Aug 21;414:186-199. doi: 10.1016/j.neuroscience.2019.06.030. Epub 2019 Jul 5.
Substantial evidence has demonstrated that prenatal stress (PS) impairs spatial learning and memory in offspring. The neuron-specific protein kinase C gamma (PKCγ) has been proposed to be unique in spatial learning and memory. The present study proposes to determine whether hippocampal PKCγ is involved in the detrimental effects of PS on spatial learning and memory in offspring, and to further explore the effects of PS-induced PKCγ-dependent growth-associated protein 43 (GAP-43) and neurogranin (Ng) phosphorylation alteration on calcium/calmodulin-dependent protein kinase II (CaMKII) activation. Prenatal restraint stress models were established, and lentivirus-mediated overexpression of PKCγ in the hippocampal CA1 area was applied. The results demonstrated that PS impaired spatial learning acquisition and memory retrieval on the Morris Water Maze test, especially in juvenile female rats. Hippocampal PKCγ membrane translocation and cytosolic PKCγ levels were decreased in PS females. The expression of phosphorylated GAP-43 (p-GAP-43) and phosphorylated Ng (p-Ng), as well as phosphorylated CaMKII (p-CaMKII), was significantly reduced in the hippocampus of PS females. Overexpression of PKCγ in the hippocampal CA1 area recovered the ability of spatial learning and memory in PS female offspring. Furthermore, enhancing PKCγ reversed PS-induced membrane and cytosolic PKCγ reduction, and restored levels of GAP-43 and Ng phosphorylation, and CaMKII activation in the hippocampus. In conclusion, PS possibly decreases hippocampal PKCγ activity, resulting in a reduction of p-GAP-43 and p-Ng, which underlies insufficient CaMKII activation, thereby impairing spatial learning and memory.
大量证据表明，产前应激（PS）会损害后代的空间学习和记忆。神经元特异性蛋白激酶 C 伽马（PKCγ）被认为在空间学习和记忆中具有独特性。本研究旨在确定海马 PKCγ是否参与 PS 对后代空间学习和记忆的有害影响，并进一步探讨 PS 诱导的 PKCγ依赖性生长相关蛋白 43（GAP-43）和神经颗粒蛋白（Ng）磷酸化改变对钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）激活的影响。建立了产前束缚应激模型，并应用慢病毒介导的 PKCγ在海马 CA1 区的过表达。结果表明，PS 损害了 Morris 水迷宫测试中的空间学习获得和记忆检索，尤其是在幼年雌性大鼠中。PS 雌性大鼠海马 PKCγ膜易位和胞质 PKCγ水平降低。PS 雌性大鼠海马中磷酸化 GAP-43（p-GAP-43）和磷酸化 Ng（p-Ng）以及磷酸化 CaMKII（p-CaMKII）的表达显著降低。在海马 CA1 区过表达 PKCγ可恢复 PS 雌性后代的空间学习和记忆能力。此外，增强 PKCγ 可逆转 PS 诱导的 PKCγ 膜和胞质减少，并恢复海马中 GAP-43 和 Ng 磷酸化以及 CaMKII 激活的水平。综上所述，PS 可能降低海马 PKCγ 活性，导致 p-GAP-43 和 p-Ng 减少，从而导致 CaMKII 激活不足，进而损害空间学习和记忆。
