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Science 333 (6051): 1903-1907

Copyright © 2011 by the American Association for the Advancement of Science

Glutamatergic and Dopaminergic Neurons Mediate Anxiogenic and Anxiolytic Effects of CRHR1

Damian Refojo,1 Martin Schweizer,1,2 Claudia Kuehne,1 Stefanie Ehrenberg,1 Christoph Thoeringer,1 Annette M. Vogl,1 Nina Dedic,1 Marion Schumacher,1 Gregor von Wolff,1 Charilaos Avrabos,1 Chadi Touma,1 David Engblom,3 Günther Schütz,3 Klaus-Armin Nave,4 Matthias Eder,1 Carsten T. Wotjak,1 Inge Sillaber,1,2 Florian Holsboer,1 Wolfgang Wurst,1,5,6,7 Jan M. Deussing1,*

Abstract: The corticotropin-releasing hormone receptor 1 (CRHR1) critically controls behavioral adaptation to stress and is causally linked to emotional disorders. Using neurochemical and genetic tools, we determined that CRHR1 is expressed in forebrain glutamatergic and {gamma}-aminobutyric acid–containing (GABAergic) neurons as well as in midbrain dopaminergic neurons. Via specific CRHR1 deletions in glutamatergic, GABAergic, dopaminergic, and serotonergic cells, we found that the lack of CRHR1 in forebrain glutamatergic circuits reduces anxiety and impairs neurotransmission in the amygdala and hippocampus. Selective deletion of CRHR1 in midbrain dopaminergic neurons increases anxiety-like behavior and reduces dopamine release in the prefrontal cortex. These results define a bidirectional model for the role of CRHR1 in anxiety and suggest that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems might lead to emotional disorders.

1 Max Planck Institute of Psychiatry, Munich, Germany.
2 Affectis Pharmaceuticals, Munich, Germany.
3 Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany.
4 Department of Neurogenetics, Max Planck Institute for Experimental Medicine, Göttingen, Germany.
5 Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Developmental Genetics, Neuherberg, Germany.
6 Technical University Weihenstephan, Institut für Entwicklungsgenetik, Neuherberg, Germany.
7 DZNE-Demenzzentrum, München, Germany.

* To whom correspondence should be addressed. E-mail: deussing{at}mpipsykl.mpg.de


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