Work

A multitransmitter, synaptic specification–segregated calyx-like synapse linking pontine pituitary adenylate cyclase–activating polypeptide neurons to forebrain-extended amygdala

Year: 2026

Type: article

Abstract: We have discovered a highly specialized innervation of the forebrain by pituitary adenylate cyclase–activating polypeptide (PACAP) immunohistochemistry originating from the brain stem that uses glutamate, acetylcholine, and PACAP, and other peptides as neurotransmitters. The parent neurons of the axons are in the Kölliker–Fuse nucleus, and their terminals form calyx-like multirelease-site synapses in the rodent forebrain extended amygdala similar to the calyx of Held in the auditory brain stem. The latter is a giant, excitatory, cup-like axo-somatic high-fidelity synapse. The PACAP-positive terminals also form enveloping axo-somatic specialization with mixed glutamatergic and cholinergic molecular identities, co-expressing vesicular glutamate transporter 1 (VGluT1), VGluT2, vesicular acetylcholine transport (VAChT), and the neuropeptides PACAP, calcitonin gene–related peptide, and neurotensin, together with calretinin in the presynaptic compartment. We identified a distinct neuronal subpopulation in the pontine Kölliker–Fuse region of the parabrachial complex that gives rise to these calyceal terminals, which engulf Protein kinase C delta (PKCδ+) / Glutamate delta receptor 1 (GluD1+) somata in the capsular central amygdala and oval bed nucleus of the stria terminalis. Strikingly, GluD1 immunolabeling is concentrated at axo-somatic contact zones apposed to VAChT+ presynaptic vesicle cluster zones but is absent from postsynaptic densities of conventional type I synapses within the same terminals. The results demonstrate a previously unrecognized multimodal calyx-like synapse in the forebrain, with parallel fast ionotropic and modulatory peptidergic neurotransmission mechanisms, which is a substrate for high-fidelity signal transmission within viscerosensory-emotional circuits.

Source: PNAS Nexus

DOI: 10.1093/pnasnexus/pgag083