1 Department of Pharmacy, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
2 Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, the State University of New York, Buffalo, NY, USA.
J Psychopharmacol. 2019 May;33(5):568-576. doi: 10.1177/0269881119832753. Epub 2019 Mar 5.
Phosphodiesterase-2 (PDE2) is a cyclic nucleotide phosphodiesterase and is highly expressed in the amygdala, which suggests its important role in anxiety-like behavior.
The present study examined whether reduced PDE2A expression in the central nucleus of the amygdala (CeA) produces anxiolytic-like effects in mice.
PDE2A knockdown in amygdaloid (AR5) cells or the CeA was established using a lentiviral vector-based siRNA system. The anxiety-like behaviors were detected by the elevated plus maze (EPM) and hole-board tests in mice. The related proteins involved in cAMP/cGMP-dependent signaling, such as specific marker VASP, CREB and BDNF were detected by immunoblot analysis.
PDE2A inhibition in AR-5 cells resulted in increases in cAMP/cGMP-related pVASP and pCREB. Behavioral tests showed that PDE2A knockdown in the CeA induced anxiolytic-like effects as evidenced by the increases in percentages of open-arm entries and time spent in the open arms in the EPM test, and the increases in head dips and time spent in head dipping in the hole-board test. However, these anxiolytic-like effects were antagonized by pre-treatment of soluble guanylyl cyclase inhibitor ODQ or adenylate cyclase inhibitor SQ. Furthermore, PDE2A knockdown significantly increased pVASP, pCREB and decreased BDNF expression in the amygdala. Pre-intra-CeA of ODQ or SQ reversed or partially prevented the effects of PDE2A knockdown on these proteins.
The results suggest that PDE2A plays a crucial role in the regulation of anxiety by the cGMP/cAMP-dependent pVASP-pCREB-BDNF signaling pathway.
磷酸二酯酶-2（PDE2）是一种环核苷酸磷酸二酯酶，在杏仁核中高度表达，这表明它在焦虑样行为中具有重要作用。
本研究旨在探讨杏仁核中央核（CeA）中 PDE2A 表达减少是否会产生类似焦虑的作用。
采用基于慢病毒载体的 siRNA 系统建立杏仁核（AR5）细胞或 CeA 中的 PDE2A 敲低。通过高架十字迷宫（EPM）和洞板试验检测小鼠的焦虑样行为。通过免疫印迹分析检测涉及 cAMP/cGMP 依赖性信号的相关蛋白，如特异性标志物 VASP、CREB 和 BDNF。
AR-5 细胞中 PDE2A 抑制导致 cAMP/cGMP 相关 pVASP 和 pCREB 增加。行为测试显示，CeA 中的 PDE2A 敲低诱导了类似焦虑的作用，表现为 EPM 测试中开放臂进入次数和开放臂时间的百分比增加，以及洞板测试中头部浸入次数和头部浸入时间的增加。然而，这些类似焦虑的作用被可溶性鸟苷酸环化酶抑制剂 ODQ 或腺苷酸环化酶抑制剂 SQ 的预处理所拮抗。此外，PDE2A 敲低显著增加了杏仁核中的 pVASP、pCREB，并降低了 BDNF 的表达。CeA 内预先注射 ODQ 或 SQ 逆转或部分阻止了 PDE2A 敲低对这些蛋白的影响。
结果表明，PDE2A 通过 cGMP/cAMP 依赖性 pVASP-pCREB-BDNF 信号通路在焦虑的调节中起着关键作用。
