Spontaneous neurotransmission signals through store-driven Ca²⁺ transients to maintain synaptic homeostasis

Spontaneous glutamate release-driven NMDA receptor activity exerts a strong influence on synaptic homeostasis. However, the properties of Ca²⁺ signals that mediate this effect remain unclear. Here, using hippocampal neurons labeled with the fluorescent Ca²⁺ probes Fluo-4 or GCAMP5, we visualized action potential-independent Ca²⁺ transients in dendritic regions adjacent to fluorescently labeled presynaptic boutons in physiological levels of extracellular Mg²⁺. These Ca²⁺ transients required NMDA receptor activity, and their propensity correlated with acute or genetically induced changes in spontaneous neurotransmitter release. In contrast, they were insensitive to blockers of AMPA receptors, L-type voltage-gated Ca²⁺ channels, or group I mGluRs. However, inhibition of Ca²⁺-induced Ca²⁺ release suppressed these transients and elicited synaptic scaling, a process which required protein translation and eukaryotic elongation factor-2 kinase activity. These results support a critical role for Ca²⁺-induced Ca²⁺ release in amplifying NMDA receptor-driven Ca²⁺ signals at rest for the maintenance of synaptic homeostasis.