Novel multi-transmitter calyx-like giant synapse revealed in the extended amygdala
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The calyx of Held, a giant excitatory cup-like axo-somatic synapse, has been historically described exclusively in the auditory brainstem. Here, using PACAP immunohistochemistry combined with confocal and tomographic electron microscopy, we report the discovery of a morphologically similar calyx-like synapse in the extended amygdala of rodents, exhibiting unique neurochemical features. This previously unrecognized structure forms massive axo-somatic terminals with mixed glutamatergic and cholinergic identities, co-expressing VGluT1, VGluT2, VAChT, and the neuropeptides PACAP, CGRP, and neurotensin, along with calretinin in the presynaptic compartment. The postsynaptic targets are a distinct subset of PKCδ-expressing neurons that co-express the synaptic adhesion molecule GluD1. Strikingly, GluD1 immunolabeling is concentrated specifically at axo-somatic contact sites apposed to VAChT+ calyceal terminals, but absent at PSD of conventional type I synapse, suggesting a specialized molecular architecture for calyceal synapse. Our findings reveal a previously unknown calyx-like synapse in the forebrain, exhibiting a unique convergence of fast and modulatory transmission with implications for transmission fidelity within emotional-viscerosensory circuits.
Significance Statement
Fast and reliable excitatory transmission is essential for neural circuits that govern rapid sensory processing. Until now, the calyx of Held synapse was the only known giant axo-somatic glutamatergic terminal in the mammalian brain. Here, we identify a previously unrecognized calyx-like synapse in the extended amygdala, a key center for emotional and autonomic integration. This massive, multimodal synapse combines glutamatergic, cholinergic, and peptidergic transmission and targets a distinct subset of PKCδ neurons. Its molecular composition, including VGLUT1/2, VAChT, PACAP, and GluD1, suggests a unique structural and functional specialization. This discovery broadens our understanding of synaptic diversity and reveals a novel anatomical substrate for high-fidelity communication in emotional-viscerosensory circuits.
