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.
Highlights
Glycine receptors, including its beta receptor subunit (GLRB), play a major role for inhibitory neurotransmission
Increased neural fear network activation during fear conditioning and increased acoustic startle reflexes were observed in risk allele carriers, qualifying as a potential intermediate phenotype of defensive system reactivity across different levels of analyses, corresponding to the Research Domain Criteria (RDoC) approach.[2]
The present paper conceptually replicated and extended these initial findings on the behavioral, neurofunctional and neurostructural level, yielding the following major findings: converging evidence was found for increased anterior insular activation in GLRB risk allele carriers in both samples despite two procedurally different fear conditioning tasks, supporting the initial report.[1]
Summary
Glycine receptors, including its beta receptor subunit (GLRB), play a major role for inhibitory neurotransmission. Fear conditioning involves multiple areas associated with defensive responding such as the (pre-) motor cortex, medial prefrontal cortex/ACC, anterior insula, amygdala, hippocampus and thalamus.[11,12]. We expected GLRB risk allele carriers to (a) exhibit increased fear network activation during two different fear conditioning tasks in regions related to the defensive system’s neuro-architecture such as the brainstem, thalamus, amygdala, hippocampus, insula, medial prefrontal cortex/ACC, and (pre-) motor cortex with different effects for the early vs late acquisition (see1), (b) show brain morphometric alterations in these areas of interest that could underlie observed functional changes, and (c) show impaired startle habituation as a subsequent behavioral outflow of enhanced defensive system reactivity. To account for T1 equilibrium effects, the first four volumes of each time
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