Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
Mol Neurobiol. 2018 Aug;55(8):7062-7071. doi: 10.1007/s12035-018-0902-6. Epub 2018 Jan 30.
Several pieces of evidence indicate that elastase-2 (ELA2; chymotrypsin-like ELA2) is an alternative pathway to the generation of angiotensin II (ANGII). Elastase-2 knockout mice (ELA2KO) exhibit alterations in the arterial blood pressure and heart rate. However, there is no data on the behavioral consequences of ELA2 deletion. In this study, we addressed this question, submitting ELA2KO and wild-type (WT) mice to several models sensitive to anxiety- and depression-like, memory, and repetitive behaviors. Our data indicates a higher incidence of barbering behavior in ELA2KO compared to WT, as well as an anxiogenic phenotype, evaluated in the elevated plus maze (EPM). While a decrease in locomotor activity was observed in ELA2KO in EPM, this feature was not the main source of variation in the other parameters analyzed. The marble-burying test (MBT) indicated increase in repetitive behavior, observed by a higher number of buried marbles. The actimeter test indicated a decrease in total activity and confirmed the increase in repetitive behavior. The spatial memory was tested by repeated exposure to the actimeter in a 24-h interval. Both ELA2KO and WT exhibited decreased activity compared to the first exposure, without any distinction between the genotypes. However, when submitted to the cued fear conditioning, ELA2KO displayed lower levels of freezing behavior in the extinction session when compared to WT, but no difference was observed during the conditioning phase. Increased levels of BDNF were found in the prefrontal cortex but not in the hippocampus of ELA2KO mice compared to WT. Finally, in silico analysis indicates that ELA2 is putatively able to cleave BDNF, and incubation of the purified enzyme with BDNF led to the degradation of the latter. Our data suggested an anxiogenic- and antidepressant-like phenotype of ELA2KO, possibly associated with increased levels of BDNF in the prefrontal cortex.
有几项证据表明，弹性蛋白酶-2（ELA2；糜蛋白酶样 ELA2）是生成血管紧张素 II（ANGII）的替代途径。弹性蛋白酶-2 敲除小鼠（ELA2KO）表现出动脉血压和心率的改变。然而，目前尚无关于 ELA2 缺失的行为后果的数据。在这项研究中，我们研究了这个问题，将 ELA2KO 和野生型（WT）小鼠分别置于几种对焦虑样和抑郁样、记忆和重复性行为敏感的模型中。我们的数据表明，与 WT 相比，ELA2KO 发生理毛行为的发生率更高，并且在高架十字迷宫（EPM）中表现出焦虑表型。虽然在 EPM 中观察到 ELA2KO 的运动活性降低，但这一特征不是分析的其他参数变化的主要来源。大理石埋藏试验（MBT）表明，重复行为增加，表现在埋藏的大理石数量增加。活动计测试表明总活动减少，并证实了重复行为的增加。空间记忆通过在 24 小时间隔内重复暴露于活动计来测试。与第一次暴露相比，ELA2KO 和 WT 的活动均减少，两种基因型之间没有区别。然而，在进行条件恐惧训练时，与 WT 相比，ELA2KO 在消退阶段的冻结行为水平较低，但在训练阶段没有观察到差异。与 WT 相比，ELA2KO 小鼠的前额叶皮层中 BDNF 水平升高，但海马体中没有差异。最后，计算机分析表明 ELA2 能够切割 BDNF，并且将纯化的酶与 BDNF 孵育导致后者降解。我们的数据表明，ELA2KO 表现出焦虑样和抗抑郁样表型，可能与前额叶皮层中 BDNF 水平升高有关。
Zotero 插件