Multiple Mechanistically Distinct Modes of Endocannabinoid Mobilization at Central Amygdala Glutamatergic Synapses

The central amygdala (CeA) is a key structure at the limbic-motor interface regulating stress responses and emotional learning. Endocannabinoid (eCB) signaling is heavily implicated in the regulation of stress-response physiology and emotional learning processes; however, the role of eCBs in the modulation of synaptic efficacy in the CeA is not well understood. Here we describe the subcellular localization of CB1 cannabinoid receptors and eCB synthetic machinery at glutamatergic synapses in the CeA and find that CeA neurons exhibit multiple mechanistically and temporally distinct modes of postsynaptic eCB mobilization. These data identify a prominent role for eCBs in the modulation of excitatory drive to CeA neurons and provide insight into the mechanisms by which eCB signaling and exogenous cannabinoids could regulate stress responses and emotional learning. •eCB signaling components are expressed at CeA glutamatergic synapses•Activation of the CB1 receptor suppresses glutamate release in the CeA•CeA neurons express calcium- and Gq-receptor-driven eCB signaling•CeA muscarinic receptors drive temporally distinct multimodal eCB release Mechanisms regulating central amygdala synaptic plasticity are poorly understood. Here, Ramikie et al. demonstrate the versatility of endocannabinoid-mediated synaptic plasticity at central amygdala glutamatergic synapses and elucidate muscarinic mechanisms regulating temporally distinct multimodal endocannabinoid release from central amygdala neurons.