Abstract
An abnormal neuronal activity in the amygdala is involved in the pathogenesis of anxiety disorders. However, little is known about the mechanisms. High-anxiety mice and low-anxiety mice, representing the innate extremes of anxiety-related behaviors, were first grouped according to their anxiety levels in the elevated plus maze test. We found that the mRNA for endothelin-1 (ET1) and ET1 B-type receptors (ETBRs) in the amygdala was down-regulated in high-anxiety mice compared with low-anxiety mice. Knocking down basolateral amygdala (BLA) ET1 expression enhanced anxiety-like behaviors, whereas over-expressing ETBRs, but not A-type receptors (ETARs), had an anxiolytic effect. The combined down-regulation of ETBR and ET1 had no additional anxiogenic effect compared to knocking down the ETBR gene alone, suggesting that BLA ET1 acts through ETBRs to regulate anxiety-like behaviors. To explore the mechanism underlying this phenomenon further, we verified that most of the ET1 and the ET1 receptors in the BLA were expressed in pyramidal neurons. The ET1–ETBR signaling pathway decreased the firing frequencies and threshold currents for the action potentials of BLA pyramidal neurons but did not alter BLA synaptic neurotransmission. Together, these results indicate that amygdalar ET1-ETBR signaling could attenuate anxiety-like behaviors by directly decreasing the excitability of glutamatergic neurons.
Highlights
The amygdala, which is composed of functionally and morphologically heterogeneous subnuclei with complex interconnectivity, is very important in modulating anxiety-related responses[5, 6]
A smaller fraction of ET1 B-type receptors (ETBRs) was expressed in basolateral amygdala (BLA) interneurons [12.2 ± 3.8%, t(18) = 10.22, P < 0.001, Fig. 3h and i]. These results indicate that most of the ETA receptor (ETAR) and ETBRs are distributed in BLA neurons, and that they are mainly expressed in pyramidal neurons, with small fractions of these receptors distributed in BLA interneurons
To directly investigate whether ET1 regulates the excitability of BLA pyramidal neurons through ETBRs, we first measured the effect of knocking down the ETBR gene via LV-ETBR shRNA transfection on the excitability of BLA pyramidal neurons, and we evaluated whether adding ET1 to the incubation solution of LV-ETBR shRNA-transfected BLA slices would produce the opposite effect
Summary
The amygdala, which is composed of functionally and morphologically heterogeneous subnuclei with complex interconnectivity, is very important in modulating anxiety-related responses[5, 6]. The mechanisms regulating glutamatergic activity in the amygdala in relation to anxiety have not been extensively studied. ET1, through its receptor ETBR, regulates the excitability of BLA pyramidal neurons and anxiety-like behaviors. Up-regulating ETBR gene expression in the BLA by using ETBR lentiviral activation particles (LV-ETBR) attenuated anxiety-related behaviors and concomitantly inhibited the excitability of BLA pyramidal neurons. These observations reveal a novel function of ET1-ETBR in the amygdala, identify a novel pathophysiological mechanism, and may suggest a target for the development of a new class of anxiolytic drugs
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