On 22 August 2019 at 13:15 Katyayani Singh will defend her doctoral thesis „Neuropsychiatric endophenotypes ‒ focusing on IgLON adhesion molecules in the mouse brain“.
Senior Research Fellow in Human Physiology Mari-Anne Philips
Senior Research Fellow in Human Physiology Kersti Lilleväli
Professor Eero Vasar
Professor Osborne Almeida, Max Planck Institute, Germany
Understanding the multifactorial pathogenesis of neuropsychiatric disorders is a considerable challenge. Modelling neuropsychiatric disorders in animals provides us a medium to explore the endophenotypes of these disorders to understand how malfunctioning neuronal circuits manifest as pathological phenotypes. Several genome wide association studies (GWAS) and expression studies have linked IgLON superfamily of cell adhesion molecules (Lsamp, Ntm, Opcml, Negr1, IgLON 5) with neuropsychiatric disorders in humans. Analyses of Lsamp and Ntm deficient mice have shown that these genes are involved in patterning of emotional and social behavior. During development, IgLON cell adhesion molecules assist fundamental neuronal communication and the establishment of circuits through morphological changes in the developing neurons, driven by dynamic rearrangements of the cytoskeleton. The role of IgLON molecules in cytoskeletal regulation during development has remained unknown until now. The goal of the present study was to address the effect of interaction between Lsamp and Ntm and the impact of Negr1 on brain structure and function using deletional mouse models. We studied morphological, anatomical and behavioral parameters related to endophenotypes of neuropsychiatric disorders in Lsamp−/− , Ntm−/− , Lsamp−/−Ntm−/− and Negr1−/− mice. This approach allowed us to gain insight into how structural alterations in the brain can influence manifestations at the behavioral level. We showed that Lsamp and Ntm adhesion molecules interact mutually with each other to coordinate early neurite sprouting, proliferation and apoptosis, which manifest at behavior in adult. Our observation on Negr1−/− mice revealed alterations in neuritogenesis and neuroanatomy, and reduced number of inhibitory interneurons in the hippocampus that may underlie the aberrant social and cognitive behavior. Additionally, we propose that the function of IgLON molecules can exhibit through cell autonomous mechanisms during initiation of neurite sprouting independent of cell-adhesion functions. Our findings expand the understanding of how IgLONs, which are candidate genes for a wide spectrum of psychiatric disorders, are involved in the regulation of neuronal circuits at the level of neuronal morphology and neuronal properties, and how they consequently impact the structural anatomy of the brain. These neuronal alterations that manifest as behavioral alterations can be viewed as endophenotypes of neuropsychiatric disorders. We have demonstrated the suitability of IgLON-deficient mice as models for psychiatric disorders. The future investigation of these models enables better understanding of the pathogenesis and treatment of neuropsychiatric disorders.