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首页> 美国卫生研究院文献>The Journal of Neuroscience >Developmental Cell Death Is Enhanced in the Cerebral Cortex of Mice Lacking the Brain Vesicular Monoamine Transporter
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Developmental Cell Death Is Enhanced in the Cerebral Cortex of Mice Lacking the Brain Vesicular Monoamine Transporter

机译：缺乏脑水泡单胺转运蛋白的小鼠的大脑皮质中发育细胞死亡增强。

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Neurotransmitters have emerged as important players in the control of programmed cell death in the cerebral cortex. We report that genetic depletion of serotonin, dopamine, and norepinephrine in mice lacking the vesicular monoamine transporter (VMAT2 KO mice) causes an increase in cell death in the superficial layers of the cingulate and retrosplenial cortices during early postnatal life (postnatal days 0–4). Electron microscopy and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling indicated that this represents a form of apoptosis. Caspase-3 and -9 are over activated in the VMAT2 KO cortex and Bcl-XL is downregulated, whereas the apoptosis-inducing factor caspase-8 and FasL/FasR pathway are not involved. Partial inhibition of serotonin or/and catecholamine synthesis by pharmacological treatments or genetic reduction of serotonin neuron number in mice lacking the transcription factor Pet-1 (pheochromocytoma 12 E26 transformation-specific) did not modify the cell death ratios in the cerebral cortex. However, when monoamine oxidase type A was invalidated in the VMAT2 KO background (VMAT2-MAOA DKO mice), increases in 5-HT levels coincided with a reduction of cell death and a normalization of Bcl-XL expression. trkB signaling is not implicated in the anti-apoptotic effects of MAOA inhibition because BDNF mRNA levels were unchanged in VMAT2-MAOA DKO mice and because the massive cell death in the cerebral cortex of trkB KO mice is also reverted by genetic invalidation of the MAOA gene. Finally the broad 5-HT2 receptor agonist (−)-2,5-dimethoxy-4-iodoamphetamine hydrochloride prevented the increase in cell death of VMAT2 KO mice. Altogether, these results suggest that high levels of serotonin, acting through 5-HT2 receptors, have neuroprotective action on cortical neurons by controlling Bcl-XL mRNA levels and that this action is independent of trkB signaling.
机译：神经递质已成为控制大脑皮层程序性细胞死亡的重要参与者。我们报告说，缺乏水泡单胺转运蛋白的小鼠（VMAT2 KO小鼠）中5-羟色胺，多巴胺和去甲肾上腺素的遗传消耗导致扣带回和脾后皮质皮层浅层细胞死亡的增加（出生后0-4天） ）。电子显微镜和末端脱氧核苷酸转移酶介导的生物素化UTP缺口末端标记表明，这代表了细胞凋亡的一种形式。 Caspase-3和-9在VMAT2 KO皮质中被过度激活，而Bcl-XL被下调，而凋亡诱导因子caspase-8和FasL / FasR途径则不参与。在缺乏转录因子Pet-1（嗜铬细胞瘤12 E26转化特异性）的小鼠中，通过药理治疗或5-羟色胺神经元数目的遗传减少可部分抑制5-羟色胺或儿茶酚胺的合成，不会改变大脑皮质的细胞死亡率。但是，当在VMAT2 KO背景（VMAT2-MAOA DKO小鼠）中使A型单胺氧化酶无效时，5-HT水平的升高与细胞死亡的减少和Bcl-XL表达的正常化相吻合。 trakB信号传导与MAOA抑制的抗凋亡作用无关，因为BDNF mRNA水平在VMAT2-MAOA DKO小鼠中没有变化，并且trkB KO小鼠大脑皮质中的大量细胞死亡也可以通过MAOA基因的遗传无效来恢复。 。最后，广泛的5-HT2受体激动剂（-）-2,5-二甲氧基-4-碘苯丙胺盐酸盐阻止了VMAT2 KO小鼠细胞死亡的增加。总而言之，这些结果表明通过5-HT 2受体起作用的高水平5-羟色胺通过控制Bcl-XL mRNA水平对皮层神经元具有神经保护作用，并且该作用独立于trkB信号传导。

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