Neurexin mediates neuropeptide release from cholinergic motor neurons through dense-core vesicle localization
TL;DR
It is reported that loss of nrx-1 increases the release of multiple NPs from cholinergic motor neurons in C. elegans and found that neurexins can regulate NP signaling, a novel mechanism to modify circuits and behaviors, and of potential importance for NRXN1 associated human conditions.
Abstract
Neurexins are critical synaptic cell adhesion molecules that play many roles in modulating neurotransmitter release and synaptic function, and are high-confidence risk genes for neurodevelopmental conditions such as autism. Understanding the function of the neurexin superfamily has been challenging in mammalian systems that have 3 genes (NRXN1-3) that encode 2-3 major isoforms, which undergo extensive alternative splicing and generate thousands of transcripts. In contrast to mammals, C. elegans has a single gene, nrx-1, encoding only long α and short γ isoforms. Neurexins canonically regulate synapse morphology and function in a neuron- and context-specific manner, through mechanisms related to release of chemical neurotransmitters and receptors. Whether neurexins (nrx-1) impact other secretory molecules such as neuropeptides (NPs) and NP containing dense-core vesicles (DCVs) is not well understood. Here, we report that loss of nrx-1 increases the release of multiple NPs from cholinergic motor neurons in C. elegans. Using tissue specific expression and degradation of endogenous NRX-1, we find that nrx-1 functions in NP release from cholinergic neurons in a cell-autonomous manner. We confirm that loss of nrx-1 impacts cholinergic active-zone number, but also find it regulates the clustering, distribution, and expression of the DCV protein, IDA-1 (PTPRN), and the DCV secretion regulator, UNC-31 (CADPS). We find that nrx-1 functions to maintain separation and juxtaposition of neurotransmitter and NP release sites and DCV localization. Loss of cholinergic excitation (unc-17) or GABAergic inhibition (unc-25) did not impact cholinergic NP release, but that the increased NP release upon loss of nrx-1 is dependent on the calcium channel unc-2. We find that neurexins can regulate NP signaling, a novel mechanism to modify circuits and behaviors, and of potential importance for NRXN1 associated human conditions.