A complex phenotype in mice with partial or complete deficiency of the NCAM protein
Date
2012-10-01
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Abstract
Sünaptiline plastilisus on aju plastilisuse üks oluline osa, mis võimaldab ajul pidevalt luua ja eemaldada rakkudevahelisi kontakte. Aju plastilisus, mis hõlmab närvikoe erinevaid morfoloogilisi muutusi, on oluline faktor nii kognitiivsetele võimetele nagu õppimine, mälu, aistingud ja teadvus kui ka meeleoluseisunditele. Neuronaalsete rakkude adhesioonimolekul (NCAM) ja tema polüsialüülitud vorm (PSA-NCAM) on valgud, mis on üheks peamisteks sünaptilise plastilisuse kujundajateks. Eelnevad uuringud kinnitavad, et NCAM molekulid on võimelised seostuma nii omavahel kui ka teiste erinevate rakupinna valkudega. Sel moel osaleb NCAM/PSA-NCAM erinevate signaalradade käivitamises ja regulatsioonis. Üheks olulisemaks NCAMi interaktsioonipartneriks on fibroblastide kasvufaktori retseptor 1 (FGFR1).
Käesoleva uurimistöö eesmärgiks oli selgitada, kuidas osaline (NCAM+/-) või täielik (NCAM-/-) NCAM/PSA-NCAMi puudumine hiirtel mõjutab nende loomade fenotüüpi; vaadeldi, kas NCAM-/- hiirte ärevuskäitumine võib olla mõjutatud nende halvenenud kognitiivsetest võimetest. Selgitamaks, milline signaalrada vastutab kognitiivsete ja milline depressioonisarnase käitumise eest, uuriti nendel hiirtel NCAM-vahendatud signaalradu, peamisi interaktsioonipartnereid ning serotonergilist süsteemi.
Antud töö tulemused kinnitasid, et NCAM-/- hiirtel esines depressioonisarnane käitumine ning olid vähenenud kognitiivsed võimed. NCAM+/- hiirtel esines samuti depressioonisarnane käitumine, kuid nende kognitiivsed võimed ei olnud kontrollhiirtega võrreldes muutunud. Selgus ka, et NCAM-/- hiirte käitumine ärevuskatsetes on mõjutatud nende halvenenud kognitiivsetest võimetest. Leiti, et nii NCAM+/- kui NCAM-/- hiirtel esinesid muutused FGFR1 aktivatsioonis, kuid erinevalt NCAM-/- hiirtest ei kaasnenud NCAM+/- hiirtel FGFR1 aktivatsiooni langusega kaltsium-kalmoduliinist sõltuvate kinaaside II ja IV (CaMKII ja IV) ning transkriptsioonifaktori CREB aktivatsiooni muutust, mis võibki olla nende loomade käitumusliku fenotüübi põhjus. Ühtlasi leiti, et NCAM puudulikkus mõjutab serotoniini transporteri ekspressiooni ning oletatavalt just vähenenud serotoniini transporteri ekspressioon võib olla nendel loomadel ilmnenud depressioonisarnase käitumise põhjuseks.
Synaptic plasticity is one of the main factors responsible for brain plasticity. For sense and consciousness, emotional behaviour and for cognitive processes, such as learning and memory, continuous activity-induced remodelling of neuronal circuits is required. Neural cell adhesion molecule (NCAM) and its polysialyted form (PSA-NCAM) are the most significant key players in synaptic plasticity, providing stable connections between cells and at the same time, remodelling synaptic networks. It has been shown that NCAM is capable of binding to a number of proteins on the cell surface including the NCAM molecule itself on the opposing cell surface. Thus, many downstream signal pathways are dependent on NCAM/PSA-NCAM-mediated cellular signalling. One of the major interaction partners of NCAM is fibroblast growth factor receptor 1 (FGFR1). The aim of this study was to explore the effect of partial (NCAM+/-) or complete (NCAM-/-) deficiency in NCAM/PSA-NCAM on the behavioural phenotype of mice and to illuminate how disrupted cognitive abilities influence NCAM-/- mice in anxiety tests. The intracellular pathway responsible for the cognitive dysfunction in the mice and those pathways implicated in the reduced ability of the mice to cope with stress were investigated by examining the main NCAM pathways and NCAM interaction partners and also alterations in the serotonergic system. The data show that NCAM-/- mice demonstrate a depression-like behaviour with altered cognitive functions. NCAM+/- mice demonstrate a depression-like behaviour without alterations in cognitive functions. The data also show that the impaired cognition of NCAM-/- mice affect their behaviour in anxiety tests. We found that both NCAM+/- and NCAM-/- mice showed reduced phosphorylation of the FGFR1 but in contrast to NCAM-/- mice, the observed behavioural phenotype in NCAM+/- mice was not associated with alterations in the basal levels of the transcription factor CREB or phosphorylated Ca2+-calmodulin-dependent protein kinase II and IV (CaMKII and CaMKIV).We also found that reduced levels of NCAM/PSA-NCAM led to alterations in the expression of the serotonin transporter. Thus, the observed depression-like phenotype in NCAM+/- or NCAM-/- mice may be caused by a reduction in expression of the serotonin transporter.
Synaptic plasticity is one of the main factors responsible for brain plasticity. For sense and consciousness, emotional behaviour and for cognitive processes, such as learning and memory, continuous activity-induced remodelling of neuronal circuits is required. Neural cell adhesion molecule (NCAM) and its polysialyted form (PSA-NCAM) are the most significant key players in synaptic plasticity, providing stable connections between cells and at the same time, remodelling synaptic networks. It has been shown that NCAM is capable of binding to a number of proteins on the cell surface including the NCAM molecule itself on the opposing cell surface. Thus, many downstream signal pathways are dependent on NCAM/PSA-NCAM-mediated cellular signalling. One of the major interaction partners of NCAM is fibroblast growth factor receptor 1 (FGFR1). The aim of this study was to explore the effect of partial (NCAM+/-) or complete (NCAM-/-) deficiency in NCAM/PSA-NCAM on the behavioural phenotype of mice and to illuminate how disrupted cognitive abilities influence NCAM-/- mice in anxiety tests. The intracellular pathway responsible for the cognitive dysfunction in the mice and those pathways implicated in the reduced ability of the mice to cope with stress were investigated by examining the main NCAM pathways and NCAM interaction partners and also alterations in the serotonergic system. The data show that NCAM-/- mice demonstrate a depression-like behaviour with altered cognitive functions. NCAM+/- mice demonstrate a depression-like behaviour without alterations in cognitive functions. The data also show that the impaired cognition of NCAM-/- mice affect their behaviour in anxiety tests. We found that both NCAM+/- and NCAM-/- mice showed reduced phosphorylation of the FGFR1 but in contrast to NCAM-/- mice, the observed behavioural phenotype in NCAM+/- mice was not associated with alterations in the basal levels of the transcription factor CREB or phosphorylated Ca2+-calmodulin-dependent protein kinase II and IV (CaMKII and CaMKIV).We also found that reduced levels of NCAM/PSA-NCAM led to alterations in the expression of the serotonin transporter. Thus, the observed depression-like phenotype in NCAM+/- or NCAM-/- mice may be caused by a reduction in expression of the serotonin transporter.
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Väitekirja elektrooniline versioon ei sisalda publikatsioone.
Keywords
loomkatsed, aju plastilisus, ärevus, fenotüüp, adhesioonimolekulid, animal experimentation, brain plasticity, anxiety, phenotype, adhesion molecules