Role of Maspardin in Hippocampal Cellular Signaling and Cognition
Master of Science (MS)
Date of Award
Mast syndrome is an autosomal recessive inherited neurological disease with severe debilitating symptoms. The disease is slowly progressive and includes neuromotor dysfunction and dementia. In mice, maspardin deletion leads to attenuation of growth and maturation of cortical neurons. The loss of maspardin is strongly associated with dementia, suggesting that maspardin plays a role in memory processing at the cellular level. However, the cellular and molecular mechanisms that underlie dementia caused by maspardin loss at the cellular and molecular levels are not known. Therefore, this research work was mainly focused on studying working memory performance of maspardin null mice and subsequently analyzing for alterations in molecular signaling in the hippocampus. Working memory was assayed by radial arm maze (RAM). Molecular biological experiments were done in the hippocampus isolated from maspardin null and age matched control mice. Paraformaldehyde fixed hippocampus was used to identify subcellular localization of maspardin. Results of RAM experiments showed 2-month-old maspardin null mice had better cognitive processing. Activity in an open field maze was compared against wild-type mice and, when allowed to explore a plus-shaped maze, maspardin null mice did not show any anxiety-like behavior. Coimmunoprecipitation and double immunofluorescence labeling studies reveal maspardin is co-localized with the early endosomal marker Rab5. Quantitative analysis of proteins in the hippocampus illustrated downregulation of brain derived neurotrophic factor (BDNF) in maspardin null mice. However, nerve growth factor (NGF) levels, Wnt/β-catenin signaling, extracellular signal regulated kinase levels, and neuroinflammation assessed by tumor necrosis factor α (TNFα) and interleukin 1β (IL1β) levels were not altered. These results suggest that maspardin co-localizes with Rab5 and, therefore, might play a role in endocytosis. Furthermore, maspardin loss in young mice did not cause cognitive impairments or other behavioral aberrations, but BDNF levels in the hippocampus were reduced, suggesting potential deterioration of cellular signaling with aging.
Biology | Cell and Developmental Biology | Life Sciences | Microbiology
Yang, Euitaek, "Role of Maspardin in Hippocampal Cellular Signaling and Cognition" (2018). Electronic Theses & Dissertations. 876.