Diacylglycerol lipase alpha in astrocytes is involved in maternal care and affective behaviors
Diacylglycerol lipase alpha in astrocytes is involved in maternal care and affective behaviors
复制标题
DOI：
10.1002/glia.23903
复制
发表时间：
2020-09-02
期刊：
影响因子：
6.2
通讯作者：
Leidmaa, Este
中科院分区：
文献类型：
--
作者：
Schuele, Lena-Louise;Glasmacher, Sandra;Leidmaa, Este
大麻素CB 1受体或二酰基甘油脂肪酶α（DAGLa）（参与内源性大麻素（eCB）2-花生四烯酸甘油（2-AG）合成的主要酶）的遗传缺失在抑郁症相关行为的动物模型中产生了深刻的表型。此外，临床研究表明，CB 1拮抗剂可增加重度抑郁发作的发生率和严重程度。然而，基本的病理机制在很大程度上是未知的。在这项研究中，我们集中在星形胶质细胞的可能参与。使用高灵敏度的RNAscope技术，我们首次发现成年小鼠大脑中的星形胶质细胞亚群表达Dagla，尽管水平较低。靶向脂质组学显示，星形胶质细胞DAGLa仅占稳态脑2-AG水平和其他花生四烯酸衍生的脂质（如拟南芥素）的一小部分。然而，Daglain成年小鼠星形胶质细胞的缺失具有深远的行为后果，抑郁样行为反应显著增加，对母体行为的影响显著，与血清孕酮和雌二醇水平升高相对应。因此，我们的研究结果表明，从DAGLa代谢轴的星形胶质细胞中的脂质在情感行为中发挥了关键的调节作用。
Genetic deletion of cannabinoid CB1 receptors or diacylglycerol lipase alpha (DAGLa), the main enzyme involved in the synthesis of the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG), produced profound phenotypes in animal models of depression-related behaviors. Furthermore, clinical studies have shown that antagonists of CB1 can increase the incidence and severity of major depressive episodes. However, the underlying pathomechanisms are largely unknown. In this study, we have focused on the possible involvement of astrocytes. Using the highly sensitive RNAscope technology, we show for the first time that a subpopulation of astrocytes in the adult mouse brain expressesDagla, albeit at low levels. Targeted lipidomics revealed that astrocytic DAGLa only accounts for a minor percentage of the steady-state brain 2-AG levels and other arachidonic acid derived lipids like prostaglandins. Nevertheless, the deletion ofDaglain adult mouse astrocytes had profound behavioral consequences with significantly increased depressive-like behavioral responses and striking effects on maternal behavior, corresponding with increased levels of serum progesterone and estradiol. Our findings therefore indicate that lipids from the DAGLa metabolic axis in astrocytes play a key regulatory role in affective behaviors.