Inhibition in the amygdala anxiety circuitry

Abstract

Inhibitory neurotransmission plays a key role in anxiety disorders, as evidenced by the anxiolytic effect of the benzodiazepine class of γ-aminobutyric acid (GABA) receptor agonists and the recent discovery of anxiety-associated variants in the molecular components of inhibitory synapses. Accordingly, substantial interest has focused on understanding how inhibitory neurons and synapses contribute to the circuitry underlying adaptive and pathological anxiety behaviors. A key element of the anxiety circuitry is the amygdala, which integrates information from cortical and thalamic sensory inputs to generate fear and anxiety-related behavioral outputs. Information processing within the amygdala is heavily dependent on inhibitory control, although the specific mechanisms by which amygdala GABAergic neurons and synapses regulate anxiety-related behaviors are only beginning to be uncovered. Here, we summarize the current state of knowledge and highlight open questions regarding the role of inhibition in the amygdala anxiety circuitry. We discuss the inhibitory neuron subtypes that contribute to the processing of anxiety information in the basolateral and central amygdala, as well as the molecular determinants, such as GABA receptors and synapse organizer proteins, that shape inhibitory synaptic transmission within the anxiety circuitry. Finally, we conclude with an overview of current and future approaches for converting this knowledge into successful treatment strategies for anxiety disorders.

Fig. 1. Inhibitory circuits of the amygdala that are implicated in the regulation of anxiety-related behavior.

The sensory information from the cortex and thalamus flows in series across the BLA and bifurcates as it enters the CeA. While recent optogenetic studies have begun to clarify the role of individual inhibitory loops of the CeA in anxiety-related behaviors, less is known about the intrinsic circuitry and downstream targets of individual types of neurons in the CeM. For simplicity, all of the afferents to the CeA apart from the BLA afferents are omitted, as well as some of the CeA downstream targets, including the dorsal vagal complex and the hypothalamus (which receives input from the CeM). Abbreviations: BLA basolateral amygdala; CALB calbindin; _LCCK large cholecystokinin; _SCCK small cholecystokinin; CeA central amygdala; CeL centrolateral amygdala; CeM centromedial amygdala; CRF corticotropin releasing factor; dPAG dorsal periaqueductal gray; HT_R2A serotonin receptor 2 A; HYP, hypothalamus LC, locus coeruleus; NK1_R neurokinin 1 receptor; OTR_, oxytocin receptor; PAG periaqueductal gray; PV parvalbumin; SOM somatostatin; Tac2 tachykinin 2; VIP vasoactive intestinal peptide; VPR vasopressin receptor

Fig. 2. Molecular determinants of anxiety-related behavior at inhibitory synapses.

a Overview of the synaptic and extrasynaptic machinery involved in mediating and regulating inhibitory neurotransmission. b Receptors that have been linked to mediating inhibitory neurotransmission in the amygdala anxiety circuitry. c Molecular components of the inhibitory postsynapse (adapted from ref). Components depicted in red represent synapse organizers that have been linked to exaggerated anxiety behaviors in humans and/or mice. Components depicted in beige represent synapse organizers that are known to be present at inhibitory synapses, but have not been linked to anxiety. Not all known inhibitory synapse organizers are depicted here; a complete list is available in refs^,. Abbreviations: BZD benzodiazepine; Cb collybistin; Cst-2 calsyntenin-2; IgSF9b immunoglobulin superfamily member 9b; NF186 neurofascin 186, Nlgn neuroligin; Nrxn neurexin; S-SCAM synaptic scaffolding molecule