Abstract
Spontaneous glutamate release-driven NMDA receptor activity exerts a strong influence on synaptic homeostasis. However, the properties of Ca(2+) signals that mediate this effect remain unclear. Here, using hippocampal neurons labeled with the fluorescent Ca(2+) probes Fluo-4 or GCAMP5, we visualized action potential-independent Ca(2+) transients in dendritic regions adjacent to fluorescently labeled presynaptic boutons in physiological levels of extracellular Mg(2+). These Ca(2+) 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 Ca(2+) channels, or group I mGluRs. However, inhibition of Ca(2+)-induced Ca(2+) 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 Ca(2+)-induced Ca(2+) release in amplifying NMDA receptor-driven Ca(2+) signals at rest for the maintenance of synaptic homeostasis.
Highlights
Studies in the last decade have shown that spontaneous release events trigger biochemical signaling leading to maturation and stability of synaptic networks, local dendritic protein synthesis and control postsynaptic responsiveness during homeostatic synaptic plasticity (Chung and Kavalali, 2006; Sutton et al, 2006; Kavalali, 2015)
Both reporters were used on hippocampal neurons that were infected with lentivirus expressing the fusion protein Synaptobrevin2-mOrange (Syb2-mOrange) consisting of a chimera of the synaptic vesicle protein synaptobrevin2 with the pH sensitive red-shifted fluorophore mOrange (Ramirez et al, 2012) (Figure 1A–D)
Fluorescence images were collected at a frequency of 10 Hz and fluorescence intensity traces were generated for the regions of interest (ROIs) selected over Syb2-mOrange puncta which fluorescence was maximized at Neuroscience the end of each experiment using 50 mM NH4Cl (Figure 1E)
Summary
Studies in the last decade have shown that spontaneous release events trigger biochemical signaling leading to maturation and stability of synaptic networks, local dendritic protein synthesis and control postsynaptic responsiveness during homeostatic synaptic plasticity (Chung and Kavalali, 2006; Sutton et al, 2006; Kavalali, 2015). Most surprisingly, these studies have demonstrated that postsynaptic excitatory receptor blockade or inhibition of neurotransmitter release in addition to action potential blockade induces faster and more pronounced homeostatic synaptic potentiation (Sutton et al, 2006; Nosyreva et al, 2013). The NMDA receptor Ca2+ influx under these conditions is estimated to be small, corresponding to approximately 20% of the full Ca2+ influx carried by
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