期刊
JOURNAL OF NEUROSCIENCE
卷 42, 期 12, 页码 2385-2403出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2207-21.2022
关键词
active zone; nanodomain; neurotransmitter release; presynaptic; synaptic vesicle fusion; voltage-gated calcium channel
资金
- National Institutes of Health [R01 MH084874, R01 NS052699]
This study investigates the number, subtypes, and locations of Ca2+ channels involved in neurotransmitter release at central synapses. By using single channel analysis and lattice light-sheet microscopy, the researchers discovered that a small pool of Ca2+ channels, comprising N-, P/Q-, and R-subtypes, are available to gate neurotransmitter release. They also found that as few as one channel may trigger neurotransmitter release. These findings provide important insights into the understanding of Ca2+ channel and synaptic dysfunction.
Efficient and reliable neurotransmission requires precise coupling between action potentials (APs), Ca2+ entry and neurotransmitter release. However, Ca2+ requirements for release, including the number of channels required, their subtypes, and their location with respect to primed vesicles, remains to be precisely defined for central synapses. Indeed, Ca2+ entry may occur through small numbers or even single open Ca(2+ )channels, but these questions remain largely unexplored in simple active zone (AZ) synapses common in the nervous system, and key to addressing Ca2+ channel and synaptic dysfunction underlying numerous neurologic and neuropsychiatric disorders. Here, we present single channel analysis of evoked AZ Ca2+ entry, using cell-attached patch clamp and lattice light-sheet microscopy (LLSM), resolving small channel numbers evoking Ca2+ entry following depolarization, at single AZs in individual central lamprey reticulospinal presynaptic terminals from male and females. We show a small pool (mean of 23) of Ca2+ channels at each terminal, comprising N-(CaV2.2), P/Q-(CaV2.1), and R-(CaV2.3) subtypes, available to gate neurotransmitter release. Significantly, of this pool only one to seven channels (mean of 4) open on depolarization. High temporal fidelity lattice light-sheet imaging reveals AP-evoked Ca2+ transients exhibiting quantal amplitude variations of 0-6 event sizes between individual APs and stochastic variation of precise locations of Ca2+ entry within the AZ. Further, total Ca2+ channel numbers at each AZ correlate to the number of presynaptic primed synaptic vesides. Dispersion of channel openings across the AZ and the similar number of primed vesides and channels indicate that Ca2+ entry via as few as one channel may trigger neurotransmitter release.
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