Role of α2δ-3 in regulating calcium channel localization at presynaptic active zones during homeostatic plasticity

The homeostatic modulation of synaptic transmission is an evolutionarily conserved mechanism that is critical for stabilizing the nervous system. At the Drosophila neuromuscular junction (NMJ), presynaptic homeostatic potentiation (PHP) compensates for impairments in postsynaptic glutamate receptors due to pharmacological blockade or genetic deletion. During PHP, there is an increase in presynaptic neurotransmitter release, counteracting postsynaptic changes and restoring excitation to baseline levels. Previous studies have shown that alpha 2 delta-3, an auxiliary subunit of voltage-gated calcium channels (VGCCs), is essential for both the rapid induction and sustained expression of PHP at the Drosophila NMJ. However, the molecular mechanisms by which alpha 2 delta-3 regulates neurotransmitter release during PHP remain to be elucidated. In this study, we utilized electrophysiological, confocal imaging, and super-resolution imaging approaches to explore how alpha 2 delta-3 regulates synaptic transmission during PHP. Our findings suggest that alpha 2 delta-3 governs PHP by controlling the localization of the calcium channel pore-forming alpha 1 subunit at presynaptic release sites, or active zones. Moreover, we examined the role of two structural domains within alpha 2 delta-3 in regulating neurotransmitter release and calcium channel localization. Our results highlight that these domains in alpha 2 delta-3 serve distinct functions in controlling synaptic transmission and presynaptic calcium channel abundance, at baseline in the absence of perturbations and during PHP. In summary, our research offers compelling evidence that alpha 2 delta-3 is an indispensable signaling component for controlling calcium channel trafficking and stabilization in homeostatic plasticity.

Automated summary

This study explores the role of alpha 2 delta-3 in the homeostatic modulation of synaptic transmission. The results suggest that alpha 2 delta-3 regulates neurotransmitter release by controlling the localization of the calcium channel alpha 1 subunit at presynaptic release sites. Furthermore, two structural domains within alpha 2 delta-3 are found to play distinct roles in synaptic transmission and presynaptic calcium channel abundance.