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Nat Med:美学者揭示microRNA与精神分裂的幻听存在关联关系

摘要 : 2016年11月29日,国际学术权威刊物自然出版集团旗下子刊《Nature Medicine》杂志在线发表了美国圣犹大儿童研究医院Stanislav Zakharenko研究员的一篇研究论文,论文报道了精神分裂症与幻听有关的大脑回路,揭示了microRNA对回路正常工作的重要性。

 2016年11月29日,国际学术权威刊物自然出版集团旗下子刊《Nature Medicine》杂志在线发表了美国圣犹大儿童研究医院Stanislav Zakharenko研究员的一篇研究论文,论文报道了精神分裂症与幻听有关的大脑回路,揭示了microRNA对回路正常工作的重要性。

研究发现,miR-338-3p是这个回路受到破坏的关键。在小鼠模型中去除这种microRNA会抑制该回路的正常功能。以这种microRNA为靶标有望开发出副作用更小的抗精神病药物。”研究人员现在通过22q11缺失综合征小鼠模型研究精神分裂症。他们发现,miR-338-3p调控蛋白Drd2的生产,而Drd2是抗精神病药物的主要靶标。当这种microRNA水平下降的时候,听觉丘脑的Drd2就会增多。研究人员指出,听觉丘脑Drd2水平提升与小鼠大脑回路受到干扰有关,精神分裂症患者的听觉丘脑也存在Drd2增加。

研究显示,miR-338-3p水平下降增加了听觉丘脑的Drd2,影响了关联丘脑和听觉皮层的大脑回路,而听觉皮层与幻听有关。在 精神分裂症患者的丘脑中,miR-338-3p水平也比较低。进一步研究表明,miR-338-3p并没有影响小鼠的其他大脑回路。这可能是因为miR-338-3p在丘脑水平特别高,是丘脑中丰度最高的microRNA之一。研究人员给小鼠的听觉丘脑补充miR-338-3p,成功减少了Drd2蛋白,使相关回路恢复正常功能。由此可见,以miR-338-3p可以开发出靶向性更强副作用更小的新型抗精神病药物。

原文链接:

Thalamic miR-338-3p mediates auditory thalamocortical disruption and its late onset in models of 22q11.2 microdeletion

原文摘要:

Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. Here we show that these auditory TC phenotypes have a delayed onset in 22q11DS mice and are associated with an age-dependent reduction of miR-338-3p, a miRNA that targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the TC abnormalities, and deletion of Mir338 (which encodes miR-338-3p) or reduction of miR-338-3p expression mimicked the TC and behavioral deficits and eliminated the age dependence of these deficits. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory TC signaling in 22q11DS mice, and it may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset.

来源: Nature Medicine 浏览次数:0

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