Abstract
The OTX2 homeoprotein transcription factor is expressed in the dopaminergic neurons of the ventral tegmental area, which projects to limbic structures controlling complex behaviors. OTX2 is also produced in choroid plexus epithelium, from which it is secreted into cerebrospinal fluid and transferred to limbic structure parvalbumin interneurons. Previously, adult male mice subjected to early-life stress were found susceptible to anxiety-like behaviors, with accompanying OTX2 expression changes in ventral tegmental area or choroid plexus. Here, we investigated the consequences of reduced OTX2 levels in Otx2 heterozygote mice, as well as in Otx2+/AA and scFvOtx2tg/0 mouse models for decreasing OTX2 transfer from choroid plexus to parvalbumin interneurons. Both male and female adult mice show anxiolysis-like phenotypes in all three models. In Otx2 heterozygote mice, we observed no changes in dopaminergic neuron numbers and morphology in ventral tegmental area, nor in their metabolic output and projections to target structures. However, we found reduced expression of parvalbumin in medial prefrontal cortex, which could be rescued in part by adult overexpression of Otx2 specifically in choroid plexus, resulting in increased anxiety-like behavior. Taken together, OTX2 synthesis by the choroid plexus followed by its secretion into the cerebrospinal fluid is an important regulator of anxiety-related phenotypes in the mouse.
| Original language | English |
|---|---|
| Journal | Molecular Psychiatry |
| ISSN | 1359-4184 |
| DOIs | |
| Publication status | Published - 2021 |
Funding
All animal housing and experimental procedures were carried out in accordance with the recommendations of the European Economic Community (2010/63/UE) and the French National Committee (2013/118). For surgical procedures, animals were anesthetized with Xylazine (Rompun 2%, 5 mg/kg) and Ketamine (Imalgene 500, 80 mg/kg) by intraperitoneal injection. This research (project no. 00704.02) was approved by Ethics committee n° 59 of the French Ministry for Research and Higher Education. Acknowledgements We would like to thank Chantal Dubreuil, Jessica Apulei, and Lucía Jiménez Alonso for technical assistance. Funding was provided by Fondation Bettencourt Schueller, European Research Council Advanced Grant (HOMEOSIGN, ERC-2013-ADG-339379 to AP), and Agence Nationale de la Recherche Grant (ANR-11-BLAN-069467 to AP).
Research Areas and Centers
- Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
