Abstract
The morphology and function of neuronal synapses are regulated by neural activity, as manifested in activity-dependent synapse maturation and various forms of synaptic plasticity. Here we employed cryo-electron tomography (cryo-ET) to visualize synaptic ultrastructure in cultured hippocampal neurons and investigated changes in subcellular features in response to chronic inactivity, a paradigm often used for the induction of homeostatic synaptic plasticity. We observed a more than 2-fold increase in the mean number of dense core vesicles (DCVs) in the presynaptic compartment of excitatory synapses and an almost 20-fold increase in the number of DCVs in the presynaptic compartment of inhibitory synapses after 2 days treatment with the voltage-gated sodium channel blocker tetrodotoxin (TTX). Short-term treatment with TTX and the N-methyl-D-aspartate receptor (NMDAR) antagonist amino-5-phosphonovaleric acid (AP5) caused a 3-fold increase in the number of DCVs within 100 nm of the active zone area in excitatory synapses but had no significant effects on the overall number of DCVs. In contrast, there were very few DCVs in the postsynaptic compartments of both synapse types under all conditions. These results are consistent with a role for presynaptic DCVs in activity-dependent synapse maturation. We speculate that these accumulated DCVs can be released upon reactivation and may contribute to homeostatic metaplasticity.
Highlights
Neural activity can profoundly shape the structure and function of synapses and plays crucial roles in the construction and reconfiguration of neuronal circuits in the brain (Goodman and Shatz, 1993; Zito and Svoboda, 2002; Dan and Poo, 2004; Espinosa and Stryker, 2012)
Under cryo-electron tomography (cryo-ET), synapses in the vitrified samples were identified based on characteristic features, including pairs of apposed membranes with relatively uniform clefts between them, and vesicles of similar sizes on one side (Figures 1A–F)
Among the 332 synapses we examined, the majority (274) were excitatory synapses (Figures 1–3), identifiable based on their distinct postsynaptic densities (PSDs; Colonnier, 1968; Peters and Palay, 1996; Tao et al, 2018), identified as a thick electrondense layer attached to the postsynaptic membrane on its cytoplasmic side (Figures 1A,C,E)
Summary
Neural activity can profoundly shape the structure and function of synapses and plays crucial roles in the construction and reconfiguration of neuronal circuits in the brain (Goodman and Shatz, 1993; Zito and Svoboda, 2002; Dan and Poo, 2004; Espinosa and Stryker, 2012). Neuronal activity participates in the process of synaptic formation through various signaling mechanisms (Andreae and Burrone, 2014) Some of these mechanisms, e.g., release of brain-derived neurotrophic factor (BDNF) and calcium influx through activation of the N-methyl-Daspartate receptor (NMDAR), are used in the induction of Hebbian synaptic plasticity in more mature synapses, such as long-term potentiation (LTP) and spike-timing-dependent plasticity (STDP; Bi and Poo, 1998; Constantine-Paton and Cline, 1998; Ying et al, 2002; Malenka and Bear, 2004). Such mechanisms involve a positive feedback process: neuronal or synaptic activation causes synaptic strengthening, which in turn leads to higher levels of activity (Bi and Poo, 2001; Fauth and Tetzlaff, 2016)
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