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

Abstract

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.

Anxiety and Startle Phenotypes in Glrb Spastic and Glra1 Spasmodic Mouse Mutants

“…Human GLRB carriers showed strong activation of the defensive system of the brain specifically in the thalamus and insula. In the early phase of fear conditioning also inverse effects have been observed indicating impaired fear inhibitory learning (Deckert et al, 2017;Lueken et al, 2017). The heterozygous spastic mice investigated in this study displayed no significant differences in the EPM or in the light-dark test.…”

“…Emotions and behavioral responses in panic disorders are encoded by a complex, not fully understood, interplay of different neural circuits in the brain (Godemann et al, 2005;Hamm et al, 2016). In humans carrying single non-coding nucleotide GLRB variants, increased startle reflexes combined with an avoidance of open spaces were the main behavioral characteristics (Deckert et al, 2017;Lueken et al, 2017).…”

Genome-wide SNP data unravel the ancestry and signatures of divergent selection in Ghurrah pigs of India

“…The strongest F ST signal for divergence was observed in a 5.25 Mb region on . This region contains GLRB, GRIA2 and GSX2 genes, the human orthologs of which are involved in synaptic transmission and nervous system development (Lueken et al, 2017;Salpietro et al, 2019). Further evidence of neurological and behavioral divergence between the breed groups was found by the results of the XP-EHH analysis (p XP-EHH ≥ 2.40, Fig.…”

A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety

“…Detailed descriptions of all samples have been published 9 , 16 , 33 , 37 . Sample characteristics are summarized in supplementary table 1 .…”

“…Statistical analysis of fMRI data was conducted as described previously 16 . On the group level, contrast images for CS+unpaired and CS− of the first and second halves of the acquisition and extinction phase were entered into a flexible factorial design treating subjects as random variables and the fMRI center as a covariate.…”