Melanie Ullrich, Maruschka Weber, Antonia Post, Sandy Popp, Jessica Grein, Martin Zechner, Hans Guerrero González, Anna Kreis, Angelika Schmitt, Nurcan Üçeyler, Klaus-Peter J. Lesch, Kai Schuh
- Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.
MetadatenAuthor: | Melanie Ullrich, Maruschka Weber, Antonia PostGND, Sandy Popp, Jessica Grein, Martin Zechner, Hans Guerrero González, Anna Kreis, Angelika Schmitt, Nurcan Üçeyler, Klaus-Peter J. LeschORCiDGND, Kai SchuhORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-491471 |
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DOI: | https://doi.org/10.1038/mp.2016.232 |
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ISSN: | 1476-5578 |
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ISSN: | 1359-4184 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/28070119 |
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Parent Title (English): | Molecular psychiatry |
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Publisher: | Macmillan |
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Place of publication: | London |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2017 |
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Date of first Publication: | 2017/01/10 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2019/02/21 |
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Tag: | Molecular biology; Neuroscience; Physiology; Psychiatric disorders |
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Volume: | 23 |
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Issue: | 2 |
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Page Number: | 15 |
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First Page: | 444 |
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Last Page: | 458 |
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Note: | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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HeBIS-PPN: | 446276251 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0 |
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