Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
Cardiovascular Institute and Warren Alpert School of Medicine at Brown University Providence, RI 02840, USA.
Brain Res. 2021 Oct 15;1769:147594. doi: 10.1016/j.brainres.2021.147594. Epub 2021 Jul 31.
Neurofibromatosis type 1 (NF1), a genetically determined neurodevelopmental disorder and tumor syndrome, is associated with cognitive impairments, including in executive function and sleep-related problems. Consistent with the human data, NF1 heterozygous (Het) mice show impaired spatial learning and memory in the water maze and extinction of contextual fear memory. It is not clear whether neurological phenotypes might depend on the parental carrier. In this study, we compared the behavioral and cognitive performance of NF1 Het and wild-type litter mates with either the father (PC) or the mother (MC) as the NF1 carrier on a F1 C57BL/66/129SvJ background. The behavioral and cognitive phenotypes and responsiveness to Alk inhibition in heterozygous NF1 offspring depended on whether the parental carrier was maternal or paternal. Alk inhibition (20 mg/kg) increased activity levels during the dark period in NF1 Het PC, but not MC, mice. In the water maze, NF1 Het PC, but not MC, mice showed reduced cognitive flexibility and impaired ability to locate the third hidden platform location, which was improved by Alk inhibition (3.6 mg/kg). Consistent with reduced cognitive flexibility, WT, but not NF1, mice showed better performance in the third than second water maze probe trial. Finally, Alk inhibition (10 mg/kg) increased baseline activity of NF1 MC, but not PC, mice during the fear conditioning test. Thus, the effective dose depends on the behavioral test and genotype but indicates that in NF1 patients cognitive flexibility might be particularly sensitive to Alk inhibition.
神经纤维瘤病 1 型（NF1）是一种遗传性神经发育障碍和肿瘤综合征，与认知障碍有关，包括执行功能和与睡眠相关的问题。与人类数据一致，NF1 杂合子（Het）小鼠在水迷宫中表现出空间学习和记忆受损，以及情境恐惧记忆的消退。目前尚不清楚神经表型是否可能取决于父母的携带者。在这项研究中，我们比较了 NF1 Het 和野生型同窝仔鼠的行为和认知表现，这些仔鼠的父亲（PC）或母亲（MC）是 NF1 携带者，在 F1 C57BL/66/129SvJ 背景下。杂合子 NF1 后代的行为和认知表型以及对 Alk 抑制的反应性取决于父母携带者是母亲还是父亲。Alk 抑制（20mg/kg）增加了 NF1 Het PC 但不增加 MC 小鼠在暗期的活动水平。在水迷宫中，NF1 Het PC 但不增加 MC 小鼠显示出认知灵活性降低和定位第三个隐藏平台位置的能力受损，而 Alk 抑制（3.6mg/kg）则改善了这一情况。与认知灵活性降低一致，WT 但不是 NF1 小鼠在第三次水迷宫探测试验中表现出更好的性能。最后，Alk 抑制（10mg/kg）增加了 NF1 MC 但不增加 PC 小鼠在恐惧条件反射测试中的基线活动。因此，有效剂量取决于行为测试和基因型，但表明在 NF1 患者中，认知灵活性可能对 Alk 抑制特别敏感。
