Neuropsychiatric endophenotypes – focusing on IgLON adhesion molecules in the mouse brain
Date
2019-07-08
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Abstract
Psühhiaatriliste häirete multifaktoriaalse patogeneesi mõistmine on suur väljakutse. Neuropsühhiaatriliste häirete modelleerimine loommudelites annab võimaluse uurida, kuidas närviringete düsfunktsionaalsus põhjustab patoloogiliste fenotüüpide avaldumist. Erinevad ülegenoomsed assotsiatsiooniuuringud (GWAS) ning ekspressiooniuuringud on näidanud IgLON perekonda kuuluvate adhesioonimolekulide (Lsamp, Ntm, Opcml, Negr1, IgLON 5) seost inimese neuropsühhiaatriliste häiretega ning käitumiskatsed Lsamp ja Ntm puudulike hiirtega on näidanud IgLON molekulide osalust emotsionaalse ja sotsiaalse käitumise kujunemises. Funktsionaalsed uuringud on näidanud, et IgLON valgud osalevad närviringete kujunemisel ja toimimisel nii arenevas kui ka täiskasvanud ajus. On teada, et tsütoskeleti dünaamilised ümberkorraldused arenevates neuronites on aluseks neuraalsete ringete kujunemisele, kuid IgLON perekonna molekulide roll arenevate neuronite tsütoskeleti reguleerimises on olnud siiani teadmata.
Käesoleva töö eesmärk oli selgitada Lsamp ja Ntm vaheliste vastastoimete ja Negr1 mõju aju struktuurile ja funktsioonidele, kasutades vastavate geenide suhtes mutantseid hiiremudeleid. Analüüsisime neuropsühhiaatriliste häiretega seotud morfoloogilisi, anatoomilisi ja käitumuslikke parameetreid Lsamp−/−, Ntm−/−, Lsamp−/−Ntm−/− ja Negr1−/− hiirtes. Mitmetasandiline lähenemine aitab selgitada, kuidas aju struktuursed kõrvalekalded mõjutavad käitumist. Näitasime, et Lsamp ja Ntm mõjutavad varajast neuriitide väljakasvu ja rakkude jagunemist ning apoptoosi teineteisest sõltuvalt ning samasugused vastasmõjud on jälgitavad ka mutanthiirte käitumuslikes reaktsioonides. Leidsime, et Negr1−/− hiirtel on kõrvalekalded neuritogeneesis, neuroanatoomias ja et nende hipokampuses on vähem inhibitoorseid neuroneid, mis võivad olla sellele hiireliinile iseloomuliku puuduliku sotsiaalse ja tunnetusliku käitumise põhjuseks. Lisaks näitavad käesoleva väitekirja tulemused, et IgLON adhesioonimolekulide toime võib olla sõltumatu rakkudevahelisest adhesioonist.
Meie uurimistulemused aitavad mõista, kuidas IgLON adhesioonivalgud, mille geenipiirkonnad on olulised riskilookused paljudele psühhiaatrilistele häiretele, reguleerivad närviringete kujunemist, mõjutades neuronite morfoloogiat ja omadusi ning aju anatoomiat. Neid neuronaalseid muutusi, mis seostuvad muutustega käitumises, võib vaadata kui psühhiaatriliste häiretega seotud endofenotüüpe. Oleme näidanud erinevate IgLON puudulikkusega hiiremudelite sobivust psühhiaatriliste häirete modelleerimiseks ning nende mudelite edasine uurimine aitab neuropsühhiaatriliste häirete kujunemist paremini mõista.
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
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
Description
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Keywords
loommudelid, psüühikahäired, ajutalitlus, hipokamp, adhesioonimolekulid