Alterations of emotional behaviour induced by the genetic invalidation of the limbic system associated membrane protein (Lsamp) – potential implications for neuropsychiatric disorders
Date
2022-09-05
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Abstract
Raku pinna neuraalsed adhesioonivalgud koordineerivad neuriitide väljakasvu, mis on aju struktuuri ja käitumisprotsesside õigeks väljaarenemiseks äärmiselt oluline. Töös uuritakse, millist mõju avaldavad hiire käitumisele ja sellega seotud biokeemilistele korrelaatidele kaks aju plastilisusega seotud IgLON perekonna neuraalset adhesioonimolekuli – limbilise süsteemiga seotud membraanivalk (Lsamp) ja selle seondumispartner neurotrimiin (Ntm).
Käesolevas doktoritöös antakse esmalt ülevaade Ntm-puudulikkusega (Ntm−/−) hiire käitumuslikust profiilist. Ntm−/− hiirtel esineb emotsionaalse õppimise häire ning kahe kõnealuse hiireliini ainsaks kattuvaks fenotüübiks oli alanenud tundlikkus d-amfetamiini liikumisaktiivsust stimuleerivale toimele. Lsamp−/− hiirtel esines suurenenud tundlikkus kokaiini ja morfiini liikumisaktiivsust stimuleerivale toimele ning samuti ülitundlikkus GABA modulaatorite sedatiivsele ja lihaseid lõõgastavale toimele. Estsitalopraami krooniline manustamine suurendas oluliselt metsiktüüpi (+/+) hiirte üldist aktiivsust ja Lsamp−/− uudistamisaktiivsust ning suunas Lsamp−/− hiirte suurenenud serotoniini (5-HT) käibe +/+ hiirtega samale tasemele. Seega, Lsamp võib avaldada olulist mõju 5-HT süsteemi sünapsite talitlusele ning 5-HT süsteem võib olla Lsamp−/− hiirte käitumises esinevate ärevuse ja sotsiaalsusega seotud muutuste neurokeemiliseks vahendajaks.
Käitumiskatsed näitasid, et kui lülitada korraga välja nii Lsamp kui ka Ntm geen (topeltmutandid), siis mõned Lsamp−/− ja Ntm−/− hiirte juures ilmnenud efektid (ujumiskiiruse vähenemine ja liikumisaktiivsuse suurenemine) võimenduvad, mis viitab Lsamp ja Ntm geenide interaktsioonidele. Sarnast interaktsiooni kinnitavad ka rakukultuuri katsed. Kokkuvõtteks, käesolev töö näitab, et Lsamp koos oma seondumispartneri Ntm-iga osaleb mitmete käitumuslike kohanemisreaktsioonide aluseks olevate virgatsaine süsteemide (dopamiini, serotoniin, GABA) aktiivsuse moduleerimises
Cell surface neural adhesion proteins are critical components in the complex orchestration of neuritogenesis, essential for proper brain construction and behaviour. Here we focus on the impact of the plasticity-associated IgLON family neural adhesion molecule - the limbic system associated membrane protein (Lsamp) and its binding partner, neurotrimin (Ntm), on mouse behaviour and underlying biochemical correlates. This thesis provides the initial behavioural characterisation of Ntm-deficient mice. These animals display none of the deviations in behaviour that were previously shown in Lsamp-deficient mice, but appear to have a deficit in emotional learning. The only overlap can be seen in the decrease of the locomotor stimulating effect of d-amphetamine in both knockout models. Tests with Lsamp-deficient mice showed increased sensitivity to the locomotor activating effects of cocaine and morphine, and hypersensitivity to the sedative and muscle relaxant effects of GABA modulators. Chronic administration of escitalopram significantly increased general activity in wild-type mice and protected exploration in Lsamp−/− mice. Escitalopram also restored the elevated 5-HT turnover of Lsamp-deficient mice to a level comparable with their wild-type littermates. We suggest that Lsamp may have an impact on the integrity of serotonergic synapses, which could be the neurochemical basis of the anxiety- and sociability-related phenotype in Lsamp-deficient mice. Behavioural phenotyping indicated test-specific interactions between Lsamp and Ntm. The reduced swimming speed and increased activity phenotypes from single-deletion lines were magnified in Lsamp/Ntm-knockout mice. Evidence from further behavioural experiments shows mutual interactions between Lsamp and Ntm. In conclusion, the current study indicates that Lsamp, establishing its impact together with its interaction partner Ntm, is involved in the modulation of major neurotransmitter systems (dopamine, serotonin, GABA) underlying adaptive behavioural responses.
Cell surface neural adhesion proteins are critical components in the complex orchestration of neuritogenesis, essential for proper brain construction and behaviour. Here we focus on the impact of the plasticity-associated IgLON family neural adhesion molecule - the limbic system associated membrane protein (Lsamp) and its binding partner, neurotrimin (Ntm), on mouse behaviour and underlying biochemical correlates. This thesis provides the initial behavioural characterisation of Ntm-deficient mice. These animals display none of the deviations in behaviour that were previously shown in Lsamp-deficient mice, but appear to have a deficit in emotional learning. The only overlap can be seen in the decrease of the locomotor stimulating effect of d-amphetamine in both knockout models. Tests with Lsamp-deficient mice showed increased sensitivity to the locomotor activating effects of cocaine and morphine, and hypersensitivity to the sedative and muscle relaxant effects of GABA modulators. Chronic administration of escitalopram significantly increased general activity in wild-type mice and protected exploration in Lsamp−/− mice. Escitalopram also restored the elevated 5-HT turnover of Lsamp-deficient mice to a level comparable with their wild-type littermates. We suggest that Lsamp may have an impact on the integrity of serotonergic synapses, which could be the neurochemical basis of the anxiety- and sociability-related phenotype in Lsamp-deficient mice. Behavioural phenotyping indicated test-specific interactions between Lsamp and Ntm. The reduced swimming speed and increased activity phenotypes from single-deletion lines were magnified in Lsamp/Ntm-knockout mice. Evidence from further behavioural experiments shows mutual interactions between Lsamp and Ntm. In conclusion, the current study indicates that Lsamp, establishing its impact together with its interaction partner Ntm, is involved in the modulation of major neurotransmitter systems (dopamine, serotonin, GABA) underlying adaptive behavioural responses.
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Keywords
animal experiments, limbic system, membrane proteins, cell adhesion molecules, emotional adaptation, behavior disorders, psychostimulants, serotonergic system