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Insulin-regulated aminopeptidase immunoreactivity is abundantly present in human hypothalamus and posterior pituitary gland, with reduced expression in paraventricular and suprachiasmatic neurons in chronic schizophrenia

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Abstract

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.

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Abbreviations

Aka:

Also known as

AT IV:

Angiotensin IV

AVP:

Arginine vasopressin

BMI:

Body mass index

CSF:

Cerebrospinal fluid

DSM-IV:

Diagnostic and statistical manual of mental disorders fourth edition

EDTA:

Ethylene diamine tetraacetic acid

Fx:

Fornix

GADPH:

Glyceraldehyde-3-phosphate dehydrogenase

GS:

Glutamine synthetase

GLUT 4:

Glucose transporter 4

IgG:

Immunoglobulin G

IRAP:

Insulin-regulated aminopeptidase

IRAP 11-P:

IRAP blocking peptide 11-P

kDA:

Kilodalton

Leu-enkephalin:

Leucine-enkephalin

LVV-H7:

Human Leu-Val-Val-hemorphin 7

MHC:

Major histocompatibility complex

Met-enkephalin:

Methionine-enkephalin

OT:

Oxytocin

OTr:

Optic tract

PBS:

Phosphate-buffered saline

PeVN:

Periventricular nucleus

PMSF:

Phenyl methylsulfonyl fluoride

PC:

Pearson’s correlation

PVN:

Paraventricular nucleus

SCN:

Suprachiasmatic nucleus

Schizo:

Schizophrenia (used in Table 3)

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

SON:

Supraoptic nucleus

SONdl:

Dorsolateral supraoptic nucleus

SONdm:

Dorsomedial supraoptic nucleus

SONvm:

Ventromedial supraoptic nucleus

TBS:

TRIS-buffered saline

TRIS:

Tris(hydroxymethyl)-aminomethane

V3:

Third ventricle

VIP:

Vasoactive intestinal peptide

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Acknowledgements

The authors wish to thank Renate Stauch for her skillful assistance.

Authors contribution

H.-G. Bernstein designed the study, participated in cell countings, wrote the article; S. Müller involved in study design, participated in cell countings; H. Dobrowolny performed biostatistics; U. Lendeckel participated in biochemical and molecular work; A. Bukowska participated in biochemical and molecular work; G. Keilhoff involved in rat experiments; A. Becker involved in rat experiments; J. Steiner involved in study design; K. Trübner contributed pituitary glands; B. Bogerts involved in study design.

Funding source

This study was funded by the University of Magdeburg (Germany).

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Medical Faculty, University of Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany

    Hans-Gert Bernstein, Susan Müller, Hendrik Dobrowolny, Johann Steiner & Bernhard Bogerts

  2. Institute of Medical Biochemistry and Molecular Biology, University Medicine, Ernst-Moritz-Arndt-University, 17475, Greifswald, Germany

    Carmen Wolke & Uwe Lendeckel

  3. EUTRAF Working Group, Molecular Electrophysiology, University Hospital Magdeburg, 39120, Magdeburg, Germany

    Alicja Bukowska

  4. Institute of Biochemistry and Cell Biology, Medical Faculty, University of Magdeburg, 39120, Magdeburg, Germany

    Gerburg Keilhoff

  5. Institute of Pharmacology and Toxicology, Medical Faculty, University of Magdeburg, 39120, Magdeburg, Germany

    Axel Becker

  6. Department for Legal Medicine, University of Duisburg-Essen, 45141, Essen, Germany

    Kurt Trübner

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  1. Hans-Gert Bernstein
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  2. Susan Müller
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Bernstein, HG., Müller, S., Dobrowolny, H. et al. Insulin-regulated aminopeptidase immunoreactivity is abundantly present in human hypothalamus and posterior pituitary gland, with reduced expression in paraventricular and suprachiasmatic neurons in chronic schizophrenia. Eur Arch Psychiatry Clin Neurosci 267, 427–443 (2017). https://doi.org/10.1007/s00406-016-0757-7

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  • DOI: https://doi.org/10.1007/s00406-016-0757-7

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