Abstract

The endocannabinoid system, comprising lipid-based signaling molecules and their G-protein coupled receptors (eCB-Rs), is a critical modulator of synaptic transmission in the central nervous system. However, its role in regulating spontaneous synaptic activity (SSA) at the peripheral neuromuscular junction (NMJ) remains poorly characterized. This study investigated the participation of eCB-Rs in modulating miniature endplate potentials (mEPPs) and miniature endplate currents (mEPCs) in isolated murine NMJ preparations using high-resolution electrophysiology. Pharmacological manipulation with selective CB1 and CB2 receptor agonists and antagonists revealed that activation of presynaptic CB1 receptors significantly reduced the frequency of SSA without altering its amplitude, suggesting a direct impact on the probability of spontaneous vesicle release. Conversely, CB2 receptor modulation showed no significant effect. Further analysis indicated that the CB1-mediated effect is dependent on the activation of voltage-gated calcium channels and involves a reduction in the readily releasable pool of synaptic vesicles. These findings establish the endocannabinoid system as a novel, potent regulator of membrane excitability and neurotransmitter release dynamics at the peripheral synapse, providing new insights into the cellular mechanisms governing neuromuscular transmission and potential therapeutic targets for neuromuscular disorders.