Sirvi Kuupäev , alustades "2010-02-26T13:34:23Z" järgi

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Depression-like phenotype and altered intracellular signalling in neural cell adhesion molecule (NCAM)-deficient mice
(Tartu University Press, 2010-02-26T13:34:23Z) Aonurm-Helm, Anu
Recent hypothesis of the pathogenesis of depression links the development of this disease with reduced brain plasticity. In the central nervous system, plasticity and connectivity in the brain are mediated by the neural cell adhesion molecule (NCAM) and its polysialylated form PSA-NCAM. Therefore, according to the plasticity theory of depression, NCAM may have a crucial role in the development of this condition. NCAM is able to bind a series of counter-receptors including fibroblast growth factor receptor (FGFR), and through the binding, activate the downstream signalling pathways, which all lead to the activation of cyclic-AMP-response element binding protein (CREB). The aim of this study was to investigate whether mice with the constitutive deficiency in NCAM exhibited dysfunctional neuronal plasticity and whether it results in the depressive-like phenotype. By using NCAM-deficient mice, NCAM interaction partners and downstream signalling pathways were studied in detail. Also was investigated, whether a synthetic peptide FGL, which mimics the actions of NCAM, is able to reverse emerged disturbances and restore the activation of intracellular signalling cascades in these animals. The results showed that NCAM deficient mice do have depression-like phenotype accompanied with reduced adult hippocampal neurogenesis. Also was seen the reduction in the activation of NCAM interaction partner FGFR and in downstream signalling pathways like calcium-calmodulin dependent kinases II and IV (CaMKII and IV) and CREB in NCAM-deficient mice. FGL peptide was able to ameliorate the signs of depressive-like behaviour, increase the neurogenesis and furthermore, FGL peptide restored the activation levels of FGFR, CaMKII, CaMKIV and CREB. The ability of FGL to modulate the levels of phosphorylated interaction partners and intracellular signalling pathways might partly explain antidepressant-like properties of the peptide.