Hufgard J R, Williams M T, Vorhees C V
Division of Neurology, Department of Pediatrics, Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Genes Brain Behav. 2017 Nov;16(8):756-767. doi: 10.1111/gbb.12391. Epub 2017 Jun 7.
Phosphodiesterase-1b (Pde1b) is highly expressed in striatum, dentate gyrus, CA3 and substantia nigra. In a new Floxed Pde1b × Cre global knockout (KO) mouse model, we show an immobility-resistance phenotype that recapitulates that found in constitutive Pde1b KO mice. We use this new mouse model to show that the resistance to acute stress-induced depression-like phenotype is not the product of changes in locomotor activity or reactivity to other stressors (learned helplessness, novelty suppressed feeding or dexamethasone suppression), and is not associated with anhedonia using the sucrose preference test. Using tamoxifen inducible Cre, we show that the immobility-resistant phenotype depends on the age of induction. The effect is present when Pde1b is Reduced from conception, P0 or P32, but not if reduced as adults (P60). We also mapped regional brain expression of PDE1B protein and of the Cre driver. These data add to the suggestion that PDE1B may be a target for drug development with therapeutic potential in depression alone or in combination with existing antidepressants.
磷酸二酯酶-1b（Pde1b）在纹状体、齿状回、CA3和黑质中高度表达。在一种新的Floxed Pde1b × Cre全球敲除（KO）小鼠模型中，我们展示了一种不动抵抗表型，该表型与组成型Pde1b KO小鼠中发现的表型相似。我们使用这种新的小鼠模型来表明，对急性应激诱导的抑郁样表型的抵抗不是运动活动变化或对其他应激源（习得性无助、新奇抑制摄食或地塞米松抑制）反应性的产物，并且使用蔗糖偏好试验表明与快感缺失无关。使用他莫昔芬诱导型Cre，我们表明不动抵抗表型取决于诱导年龄。当Pde1b从受孕、出生后第0天或第32天开始减少时，这种效应就会出现，但如果在成年期（出生后第60天）减少则不会出现。我们还绘制了PDE1B蛋白和Cre驱动蛋白在大脑中的区域表达图谱。这些数据进一步表明，PDE1B可能是药物开发的靶点，单独或与现有抗抑郁药联合使用时具有治疗抑郁症的潜力。
