University of Oulu

Henri Leinonen, Hennariikka Koivisto, Henna-Riikka Lipponen, Anna Matilainen, Antti M. Salo, Elitsa Y. Dimova, Elina Hämäläinen, Saara Stavén, Pasi Miettinen, Johanna Myllyharju, Peppi Koivunen, Heikki Tanila, Null mutation in P4h-tm leads to decreased fear and anxiety and increased social behavior in mice, Neuropharmacology, Volume 153, 2019, Pages 63-72, ISSN 0028-3908,

Null mutation in P4h-tm leads to decreased fear and anxiety and increased social behavior in mice

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Author: Leinonen, Henri1,2; Koivisto, Hennariikka1; Lipponen, Henna-Riikka1;
Organizations: 1A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
2Department of Ophthalmology, University of California–Irvine, Irvine, Ca, USA
3Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 10.5 MB)
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Language: English
Published: Elsevier, 2019
Publish Date: 2020-04-25


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.

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Series: Neuropharmacology
ISSN: 0028-3908
ISSN-E: 1873-7064
ISSN-L: 0028-3908
Volume: 153
Pages: 63 - 72
DOI: 10.1016/j.neuropharm.2019.04.023
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Dataset Reference: The following are the Supplementary data to this article:
Copyright information: © 2019 Elsevier Ltd. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license