Aonurm-Helm Anu, Anier Kaili, Zharkovsky Tamara, Castrén Eero, Rantamäki Tomi, Stepanov Vladimir, Järv Jaak, Zharkovsky Alexander
Institute of Biomedicine and Translational Medicine, Department of Pharmacology, University of Tartu, 50411 Tartu, Estonia.
Institute of Biomedicine and Translational Medicine, Department of Pharmacology, University of Tartu, 50411 Tartu, Estonia.
Eur Neuropsychopharmacol. 2015 Dec;25(12):2394-403. doi: 10.1016/j.euroneuro.2015.10.001. Epub 2015 Oct 21.
Mood disorders are associated with alterations in serotonergic system, deficient BDNF (brain-derived neurotrophic factor) signaling and abnormal synaptic plasticity. Increased degradation and reduced functions of NCAM (neural cell adhesion molecule) have recently been associated with depression and NCAM deficient mice show depression-related behavior and impaired learning. The aim of the present study was to investigate potential changes in serotonergic and BDNF systems in NCAM knock-out mice. Serotonergic nerve fiber density and SERT (serotonin transporter) protein levels were robustly reduced in the hippocampus, prefrontal cortex and basolateral amygdala of adult NCAM(-)(/-) mice. This SERT reduction was already evident during early postnatal development. [(3)H]MADAM binding experiments further demonstrated reduced availability of SERT in cell membranes of NCAM(-)(/-) mice. Moreover, the levels of serotonin and its major metabolite 5-HIAA were down regulated in the brains of NCAM(-)(/-) mice. NCAM(-)(/-) mice also showed a dramatic reduction in the BDNF protein levels in the hippocampus and prefrontal cortex. This BDNF deficiency was associated with reduced phosphorylation of its receptor TrkB. Importantly, chronic administration of antidepressant amitriptyline partially or completely restored these changes in serotonergic and BDNF systems, respectively. In conclusion, NCAM deficiency lead to prominent and persistent abnormalities in brain serotonergic and BDNF systems, which likely contributes to the behavioral and neurobiological phenotype of NCAM(-/-) mice.
情绪障碍与血清素能系统改变、脑源性神经营养因子（BDNF）信号传导缺陷及异常的突触可塑性有关。神经细胞黏附分子（NCAM）降解增加和功能降低最近被认为与抑郁症有关，NCAM基因敲除小鼠表现出与抑郁相关的行为及学习障碍。本研究的目的是调查NCAM基因敲除小鼠血清素能和BDNF系统的潜在变化。成年NCAM(-/-)小鼠海马体、前额叶皮质和基底外侧杏仁核中的血清素能神经纤维密度和血清素转运体（SERT）蛋白水平显著降低。这种SERT减少在出生后早期发育阶段就已很明显。[³H]MADAM结合实验进一步证明NCAM(-/-)小鼠细胞膜中SERT的可用性降低。此外，NCAM(-/-)小鼠大脑中血清素及其主要代谢物5-羟吲哚乙酸（5-HIAA）的水平下调。NCAM(-/-)小鼠海马体和前额叶皮质中的BDNF蛋白水平也显著降低。这种BDNF缺乏与其受体TrkB的磷酸化减少有关。重要的是，长期给予抗抑郁药阿米替林分别部分或完全恢复了血清素能和BDNF系统的这些变化。总之，NCAM缺乏导致大脑血清素能和BDNF系统出现显著且持续的异常，这可能导致了NCAM(-/-)小鼠的行为和神经生物学表型。
