Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland.
BMC Neurosci. 2010 Jun 8;11:70. doi: 10.1186/1471-2202-11-70.
Neurogenesis in the hippocampal dentate gyrus and the subventricular zone occurs throughout the life of mammals and newly generated neurons can integrate functionally into established neuronal circuits. Neurogenesis levels in the dentate gyrus are modulated by changes in the environment (enrichment, exercise), hippocampal-dependent tasks, NMDA receptor (NMDAR) activity, sonic hedgehog (SHH) and/or other factors.
previously, we showed that Protease Nexin-1 (PN-1), a potent serine protease inhibitor, regulates the NMDAR availability and activity as well as SHH signaling. Compared with wild-type (WT), we detected a significant increase in BrdU-labeled cells in the dentate gyrus of mice lacking PN-1 (PN-1 -/-) both in controls and after running exercise. Patched homologue 1 (Ptc1) and Gli1 mRNA levels were higher and Gli3 down-regulated in mutant mice under standard conditions and to a lesser extent after running exercise. However, the number of surviving BrdU-positive cells did not differ between WT and PN-1 -/- animals. NMDAR availability was altered in the hippocampus of mutant animals after exercise.
All together our results indicate that PN-1 controls progenitors proliferation through an effect on the SHH pathway and suggest an influence of the serpin on the survival of newly generated neurons through modulation of NMDAR availability.
在哺乳动物的整个生命周期中，海马齿状回和侧脑室下区都存在神经发生，并且新生成的神经元可以功能性地整合到已建立的神经元回路中。齿状回中的神经发生水平受环境变化（丰富、运动）、海马依赖性任务、NMDA 受体（NMDAR）活性、 sonic hedgehog（SHH）和/或其他因素的调节。
以前，我们表明蛋白酶 Nexin-1（PN-1），一种有效的丝氨酸蛋白酶抑制剂，调节 NMDAR 的可用性和活性以及 SHH 信号。与野生型（WT）相比，我们在缺乏 PN-1（PN-1 -/-）的小鼠的齿状回中检测到 BrdU 标记细胞的数量在对照和跑步运动后均显著增加。在标准条件下， patched 同源物 1（Ptc1）和 Gli1 mRNA 水平在突变小鼠中升高，Gli3 下调，但在跑步运动后下调程度较小。然而，WT 和 PN-1 -/-动物之间存活的 BrdU 阳性细胞数量没有差异。运动后突变动物的海马中 NMDAR 的可用性发生改变。
综上所述，我们的研究结果表明 PN-1 通过对 SHH 途径的影响来控制祖细胞的增殖，并表明该丝氨酸蛋白酶对 NMDAR 可用性的调节对新生成的神经元的存活有影响。
