Role of the parental NF1 carrier in effects of pharmacological inhibition of anaplastic lymphoma kinase in Neurofibromatosis 1 mutant mice

التفاصيل البيبلوغرافية
العنوان: Role of the parental NF1 carrier in effects of pharmacological inhibition of anaplastic lymphoma kinase in Neurofibromatosis 1 mutant mice
المؤلفون: Joseph B. Weiss, Jacob Raber, Destine Krenik
المصدر: Brain Research. 1769:147594
بيانات النشر: Elsevier BV, 2021.
سنة النشر: 2021
مصطلحات موضوعية: Male, Parents, Heterozygote, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Neurofibromatosis 1, Genotype, Offspring, Carbazoles, Antineoplastic Agents, Water maze, Biology, Mice, Cognition, Neurodevelopmental disorder, Piperidines, Internal medicine, medicine, Animals, Anaplastic lymphoma kinase, Anaplastic Lymphoma Kinase, Cognitive Dysfunction, Fear conditioning, Effects of sleep deprivation on cognitive performance, Enzyme Inhibitors, Neurofibromatosis, Maze Learning, Molecular Biology, Neurofibromin 1, Behavior, Animal, Dose-Response Relationship, Drug, General Neuroscience, Cognitive flexibility, Fear, medicine.disease, nervous system diseases, Mice, Inbred C57BL, Endocrinology, Female, Neurology (clinical), Developmental Biology
الوصف: 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.
تدمد: 0006-8993
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::38b49652d4f5a917c12ae3afdda2725aTest
https://doi.org/10.1016/j.brainres.2021.147594Test
حقوق: CLOSED
رقم الانضمام: edsair.doi.dedup.....38b49652d4f5a917c12ae3afdda2725a
قاعدة البيانات: OpenAIRE