Bernstein Hans-Gert, Müller Susan, Dobrowolny Hendrik, Wolke Carmen, Lendeckel Uwe, Bukowska Alicja, Keilhoff Gerburg, Becker Axel, Trübner Kurt, Steiner Johann, Bogerts Bernhard
Department of Psychiatry and Psychotherapy, Medical Faculty, University of Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany.
Institute of Medical Biochemistry and Molecular Biology, University Medicine, Ernst-Moritz-Arndt-University, 17475, Greifswald, Germany.
Eur Arch Psychiatry Clin Neurosci. 2017 Aug;267(5):427-443. doi: 10.1007/s00406-016-0757-7. Epub 2016 Dec 29.
The vasopressin- and oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP) is expressed in various organs including the brain. However, knowledge about its presence in human hypothalamus is fragmentary. Functionally, for a number of reasons (genetic linkage, hydrolysis of oxytocin and vasopressin, its role as angiotensin IV receptor in learning and memory and others) IRAP might play a role in schizophrenia. We studied the regional and cellular localization of IRAP in normal human brain with special emphasis on the hypothalamus and determined numerical densities of IRAP-expressing cells in the paraventricular, supraoptic and suprachiasmatic nuclei in schizophrenia patients and controls. By using immunohistochemistry and Western blot analysis, IRAP was immunolocalized in postmortem human brains. Cell countings were performed to estimate numbers and numerical densities of IRAP immunoreactive hypothalamic neurons in schizophrenia patients and control cases. Shape, size and regional distribution of IRAP-expressing cells, as well the lack of co-localization with the glia marker glutamine synthetase, show that IRAP is expressed in neurons. IRAP immunoreactive cells were observed in the hippocampal formation, cerebral cortex, thalamus, amygdala and, abundantly, hypothalamus. Double labeling experiments (IRAP and oxytocin/neurophysin 1, IRAP with vasopressin/neurophysin 2) revealed that IRAP is present in oxytocinergic and in vasopressinergic neurons. In schizophrenia patients, the numerical density of IRAP-expressing neurons in the paraventricular and the suprachiasmatic nuclei is significantly reduced, which might be associated with the reduction in neurophysin-containing neurons in these nuclei in schizophrenia. The pathophysiological role of lowered hypothalamic IRAP expression in schizophrenia remains to be established.
血管加压素和催产素降解酶胰岛素调节氨肽酶（IRAP）在包括大脑在内的多种器官中表达。然而，关于其在人类下丘脑的存在情况的了解尚不完整。在功能上，由于多种原因（基因连锁、催产素和血管加压素的水解、其作为血管紧张素IV受体在学习和记忆中的作用等），IRAP可能在精神分裂症中发挥作用。我们研究了IRAP在正常人类大脑中的区域和细胞定位，特别关注下丘脑，并确定了精神分裂症患者和对照组室旁核、视上核和视交叉上核中表达IRAP的细胞的数值密度。通过免疫组织化学和蛋白质印迹分析，IRAP在死后人类大脑中被免疫定位。进行细胞计数以估计精神分裂症患者和对照病例中IRAP免疫反应性下丘脑神经元的数量和数值密度。表达IRAP的细胞的形状、大小和区域分布，以及与胶质细胞标记物谷氨酰胺合成酶的共定位缺失，表明IRAP在神经元中表达。在海马结构、大脑皮层、丘脑、杏仁核以及大量的下丘脑中观察到了IRAP免疫反应性细胞。双重标记实验（IRAP与催产素/神经垂体素1、IRAP与血管加压素/神经垂体素2）显示IRAP存在于催产素能神经元和血管加压素能神经元中。在精神分裂症患者中，室旁核和视交叉上核中表达IRAP的神经元的数值密度显著降低，这可能与精神分裂症中这些核团中含神经垂体素的神经元减少有关。下丘脑IRAP表达降低在精神分裂症中的病理生理作用仍有待确定。
