Ehret Fanny, Moreno Traspas Ricardo, Neumuth Marie-Theres, Hamann Bianca, Lasse Daniela, Kempermann Gerd
German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany.
Center for Regenerative Therapies Dresden, TU Dresden, Dresden, Germany.
Front Aging Neurosci. 2021 May 21;13:617733. doi: 10.3389/fnagi.2021.617733. eCollection 2021.
We and others have reported that Notch3 is a regulator of adult hippocampal neurogenesis. (CADASIL), the most common genetic form of vascular dementia, is caused by mutations in . The present study intended to investigate whether there is a correlation between altered adult hippocampal neurogenesis and spatial memory performance in CADASIL transgenic mice. To overcome visual disabilities that hampered behavioral testing of the original mice (on an FVB background) we back-crossed the existing TgN3 CADASIL mouse model onto the C57BL/6J background. These animals showed an age-dependent increase in the pathognomonic granular osmiophilic material (GOM) deposition in the hippocampus. Analysis in the Morris water maze task at an age of 6 and 12 months revealed deficits in re-learning and perseverance in the CADASIL transgenic mice. Overexpression of Notch3 alone resulted in deficits in the use of spatial strategies and diminished adult neurogenesis in both age groups. The additional CADASIL mutation compensated the effect on strategy usage but not on adult neurogenesis. In brain bank tissue samples from deceased CADASIL patients we found signs of new neurons, as assessed by calretinin immunohistochemistry, but no conclusive quantification was possible. In summary, while our study confirmed the role of Notch3 in adult neurogenesis, we found a specific effect of the CADASIL mutation only on the reversion of the Notch3 effect on behavior, particularly visible at 6 months of age, consistent with a loss of function. The mutation did not revert the Notch3-dependent changes in adult neurogenesis or otherwise affected adult neurogenesis in this model.
我们和其他研究人员已报道，Notch3是成年海马神经发生的调节因子。常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病（CADASIL）是血管性痴呆最常见的遗传形式，由[相关基因]突变引起。本研究旨在调查CADASIL转基因小鼠中成年海马神经发生改变与空间记忆表现之间是否存在关联。为克服妨碍对原代小鼠（FVB背景）进行行为测试的视觉障碍，我们将现有的TgN3 CADASIL小鼠模型回交到C57BL/6J背景。这些动物海马中特征性的嗜锇颗粒物质（GOM）沉积呈现年龄依赖性增加。在6个月和12个月龄时进行的莫里斯水迷宫任务分析显示，CADASIL转基因小鼠在重新学习和坚持方面存在缺陷。单独的Notch3过表达导致两个年龄组在空间策略使用方面存在缺陷且成年神经发生减少。额外的CADASIL突变补偿了对策略使用的影响，但未补偿对成年神经发生的影响。在已故CADASIL患者的脑库组织样本中，通过钙视网膜蛋白免疫组化评估，我们发现了新神经元的迹象，但无法进行确切量化。总之，虽然我们的研究证实了Notch3在成年神经发生中的作用，但我们发现CADASIL突变仅对Notch3对行为的影响产生逆转作用，这种作用在6个月龄时尤为明显，这与功能丧失一致。该突变并未逆转Notch3依赖的成年神经发生变化，也未以其他方式影响该模型中的成年神经发生。
