A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, University of California-Irvine, Irvine, Ca, USA.
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Neuropharmacology. 2019 Jul 15;153:63-72. doi: 10.1016/j.neuropharm.2019.04.023. Epub 2019 Apr 25.
HIF prolyl 4-hydroxylases (HIF-P4Hs, also known as PHDs and EGLNs) are crucial enzymes that modulate the hypoxia inducible factor (HIF) response and help to maintain cellular oxygen homeostasis. This function is especially well-known for cytoplasmic or nuclear enzymes HIF-P4H-1-3 (PHDs 1-3, EGLNs 2, 1 and 3, respectively), but the physiological role is still obscure for a fourth suggested HIF-P4H, P4H-TM that is a transmembrane protein and resides in the endoplasmic reticulum. Recently however, both experimental and clinical evidence of the P4H-TM involvement in CNS physiology has emerged. In this study, we first investigated the expression pattern of P4H-TM in the mouse brain and found a remarkably selective abundance in brains areas that are involved in social behaviors and anxiety including amygdala, lateral septum and bed nucleus of stria terminalis. Next, we performed behavioral assays in P4h-tm mice to investigate a possible phenotype associated to these brain areas. In locomotor activity tests, we found that P4h-tm mice were significantly more active than their wild-type (WT) littermate mice, and habituation to test environment did not abolish this effect. Instead, spatial learning and memory seemed normal in P4h-tm mice as assessed by Morris swim task. In several tests assessing anxiety and fear responses, P4h-tm mice showed distinct courageousness, and they presented increased interaction towards fellow mice in social behavior tests. Most strikingly, P4h-tm mice practically lacked behavioral despair response, a surrogate marker of depression, in forced swim and tail suspension tests. Instead, mutant mice of all other Hif-p4h isoforms lacked such a behavioral phenotype. In summary, this study presents a remarkable anatomy-physiology association between the brain expression of P4H-TM and the behavioral phenotype in P4h-tm mice. Future studies will reveal whether P4H-TM may serve as a novel target for anti-depressant and anti-anxiety pharmacotherapy.
缺氧诱导因子脯氨酰羟化酶（HIF-P4Hs，也称为 PHDs 和 EGLNs）是调节缺氧诱导因子（HIF）反应的关键酶，有助于维持细胞的氧稳态。这种功能在细胞质或核酶 HIF-P4H-1-3（PHD 1-3、EGLN 2、1 和 3）中尤为明显，但对于第四种被认为是 HIF-P4H 的 P4H-TM 的生理作用仍然不清楚，P4H-TM 是一种跨膜蛋白，位于内质网中。然而，最近出现了 P4H-TM 参与中枢神经系统生理学的实验和临床证据。在这项研究中，我们首先研究了 P4H-TM 在小鼠大脑中的表达模式，发现其在参与社交行为和焦虑的大脑区域中表现出明显的选择性丰度，包括杏仁核、外侧隔核和终纹床核。接下来，我们在 P4h-tm 小鼠中进行了行为测试，以研究与这些大脑区域相关的可能表型。在运动活动测试中，我们发现 P4h-tm 小鼠比其野生型（WT）同窝小鼠明显更活跃，并且对测试环境的适应不能消除这种效应。相反，P4h-tm 小鼠的空间学习和记忆似乎正常，如 Morris 游泳任务评估所示。在几项评估焦虑和恐惧反应的测试中，P4h-tm 小鼠表现出明显的勇敢，它们在社交行为测试中表现出对同伴的互动增加。最引人注目的是，P4h-tm 小鼠在强迫游泳和悬尾测试中几乎没有表现出行为绝望反应，这是抑郁的替代标志物。相反，所有其他 Hif-p4h 同工型的突变小鼠都没有这种行为表型。总之，这项研究在 P4H-TM 在大脑中的表达与 P4h-tm 小鼠的行为表型之间呈现出显著的解剖-生理学关联。未来的研究将揭示 P4H-TM 是否可作为抗抑郁和抗焦虑药物治疗的新靶点。
