Modulation of defensive reactivity by GLRB allelic variation : converging evidence from an intermediate phenotype approach

  • Representing a phylogenetically old and very basic mechanism of inhibitory neurotransmission, glycine receptors have been implicated in the modulation of behavioral components underlying defensive responding toward threat. As one of the first findings being confirmed by genome-wide association studies for the phenotype of panic disorder and agoraphobia, allelic variation in a gene coding for the glycine receptor beta subunit (GLRB) has recently been associated with increased neural fear network activation and enhanced acoustic startle reflexes. On the basis of two independent healthy control samples, we here aimed to further explore the functional significance of the GLRB genotype (rs7688285) by employing an intermediate phenotype approach. We focused on the phenotype of defensive system reactivity across the levels of brain function, structure, and physiology. Converging evidence across both samples was found for increased neurofunctional activation in the (anterior) insular cortex in GLRB risk allele carriers and altered fear conditioning as a function of genotype. The robustness of GLRB effects is demonstrated by consistent findings across different experimental fear conditioning paradigms and recording sites. Altogether, findings provide translational evidence for glycine neurotransmission as a modulator of the brain’s evolutionary old dynamic defensive system and provide further support for a strong, biologically plausible candidate intermediate phenotype of defensive reactivity. As such, glycine-dependent neurotransmission may open up new avenues for mechanistic research on the etiopathogenesis of fear and anxiety disorders.
Author:Ulrike Lüken, Manuel Kuhn, Yunbo Yang, Benjamin Straube, Tilo Kircher, Hans-Ulrich Wittchen, Bettina Pfleiderer, Volker Arolt, André Wittmann, Andreas Ströhle, Heike Weber, Andreas ReifORCiDGND, Katharina Domschke, Jürgen Deckert, Tina B. Lonsdorf
Pubmed Id:
Parent Title (English):Translational Psychiatry
Publisher:Nature Publishing Group
Place of publication:London
Document Type:Article
Year of Completion:2017
Date of first Publication:2017/09/05
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/06/05
Tag:Clinical genetics; Learning and memory
Issue:9, e1227
Page Number:10
First Page:1
Last Page:10
Rights and permissions: Creative Commons BYThis work is licensed under a Creative Commons Attribution 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
Institutes:Medizin / Medizin
Dewey Decimal Classification:1 Philosophie und Psychologie / 15 Psychologie / 150 Psychologie
Licence (German):License LogoCreative Commons - Namensnennung 4.0