Genetically driven brain serotonin deficiency facilitates panic-like escape behavior in mice

Waider J, Popp S, Lange MD, Kern R, Kolter JF, Kobler J, Donner NC, Lowe KR, Malzbender JH, Brazell CJ, Arnold MR, Aboagye B, Schmitt-Böhrer A, Lowry CA, Pape HC, Lesch KP

Abstract

Multiple lines of evidence implicate brain serotonin (5-hydroxytryptamine; 5-HT) system dysfunction in the pathophysiology of stressor-related and anxiety disorders. Here we investigate the influence of constitutively deficient 5-HT synthesis on stressor-related anxiety-like behaviors using Tryptophan hydroxylase 2 (Tph2) mutant mice. Functional assessment of c-Fos after associated foot shock, electrophysiological recordings of GABAergic synaptic transmission, differential expression of theSlc6a4gene in serotonergic neurons were combined with locomotor and anxiety-like measurements in different contextual settings. Our findings indicate that constitutiveTph2inactivation and consequential lack of 5-HT synthesis inTph2null mutant mice (Tph2−/−) results in increased freezing to associated foot shock and a differential c-Fos activity pattern in the basolateral complex of the amygdala. This is accompanied by altered GABAergic transmission as observed by recordings of inhibitory postsynaptic currents on principal neurons in the basolateral nucleus, which may explain increased fear associated with hyperlocomotion and escape-like responses in aversive inescapable contexts. In contrast, lifelong 5-HT deficiency as observed inTph2heterozygous mice (Tph+/−) is able to be compensated through reduced GABAergic transmission in the basolateral nucleus of the amygdala based onSlc6a4mRNA upregulation in subdivisions of dorsal raphe neurons. This results in increased activity of the basolateral nucleus of the amygdala due to associated foot shock. In conclusion, our results reflect characteristic syndromal dimensions of panic disorder and agoraphobia. Thus, constitutive lack of 5-HT synthesis influence the risk for anxiety- and stressor-related disorders including panic disorder and comorbid agoraphobia through the absence of GABAergic-dependent compensatory mechanisms in the basolateral nucleus of the amygdala.