Shao Jiajie, Liewald Jana F, Steuer Costa Wagner, Ruse Christiane, Gruber Jens, Djamshedzad Mohammad S, Gebhardt Wulf, Gottschalk Alexander
Faculty of Molecular Sciences, Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany.
Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt, Germany.
PLoS Biol. 2025 May 8;23(5):e3003171. doi: 10.1371/journal.pbio.3003171. eCollection 2025 May.
Chemical synaptic transmission at the neuromuscular junction (NMJ) is regulated by electrical activity of the motor circuit, but may also be affected by neuromodulation. Here, we assessed the role of neuropeptide signaling in the plasticity of NMJ function in Caenorhabditis elegans. We show that the CAPS (Ca2+-dependent activator protein for secretion) ortholog UNC-31, which regulates exocytosis of dense core vesicles, affects both pre- and post-synaptic functional properties, as well as NMJ-mediated locomotion. Despite reduced evoked acetylcholine (ACh) transmission, the loss of unc-31 results in a more vigorous response to presynaptic stimulation, i.e., enhanced muscle contraction and Ca2+ transients. Based on expression profiles, we identified neuropeptides involved in both cholinergic (FLP-6, FLP-15, NLP-9, NLP-15, NLP-21, and NLP-38) and GABAergic motor neurons (FLP-15, NLP-15), that mediate normal transmission at the NMJ. In the absence of these peptides, neurons fail to upregulate their ACh output in response to increased cAMP signaling; for flp-15; nlp-15 double mutants, we observed overall increased postsynaptic currents, indicating that these neuropeptides may be inhibitory. We also identified proprotein convertases encoded by aex-5/kpc-3 and egl-3/kpc-2 that act synergistically to generate these neuropeptides. We propose that postsynaptic homeostatic scaling, mediated by increased muscle activation, likely through excitability, might compensate for the reduced cholinergic transmission in mutants affected for neuropeptide signaling, thus maintaining net synaptic strength. We show that in the absence of UNC-31 muscle excitability is modulated by upregulating the expression of the muscular L-type voltage-gated Ca2+ channel EGL-19. Our results unveil a role for neuropeptidergic regulation in synaptic plasticity, linking changes in presynaptic transmission to compensatory changes in muscle excitability.
神经肌肉接头（NMJ）处的化学突触传递受运动回路电活动的调节，但也可能受到神经调节的影响。在此，我们评估了神经肽信号在秀丽隐杆线虫NMJ功能可塑性中的作用。我们发现，调节致密核心囊泡胞吐作用的CAPS（Ca2+依赖性分泌激活蛋白）直系同源物UNC-31，会影响突触前和突触后的功能特性，以及NMJ介导的运动。尽管诱发的乙酰胆碱（ACh）传递减少，但unc-31的缺失会导致对突触前刺激的反应更加剧烈，即增强肌肉收缩和Ca2+瞬变。基于表达谱，我们鉴定出参与胆碱能（FLP-6、FLP-15、NLP-9、NLP-15、NLP-21和NLP-38）和GABA能运动神经元（FLP-15、NLP-15）的神经肽，它们介导NMJ处的正常传递。在没有这些肽的情况下，神经元无法响应增加的cAMP信号而上调其ACh输出；对于flp-15；nlp-15双突变体，我们观察到突触后电流总体增加，表明这些神经肽可能具有抑制作用。我们还鉴定出由aex-5/kpc-3和egl-3/kpc-2编码的前体蛋白转化酶，它们协同作用产生这些神经肽。我们提出，由肌肉激活增加介导的突触后稳态缩放，可能通过兴奋性，来补偿神经肽信号受影响的突变体中胆碱能传递的减少，从而维持净突触强度。我们表明，在没有UNC-31的情况下，通过上调肌肉L型电压门控Ca2+通道EGL-19的表达来调节肌肉兴奋性。我们的结果揭示了神经肽能调节在突触可塑性中的作用，将突触前传递的变化与肌肉兴奋性的补偿性变化联系起来。
