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Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation.
Comm. Biol. 4:666 (2021)
Calcium dynamics control synaptic transmission. Calcium triggers synaptic vesicle fusion, determines release probability, modulates vesicle recycling, participates in long-term plasticity and regulates cellular metabolism. Mitochondria, the main source of cellular energy, serve as calcium signaling hubs. Mitochondrial calcium transients are primarily determined by the balance between calcium influx, mediated by the mitochondrial calcium uniporter (MCU), and calcium efflux through the sodium/lithium/calcium exchanger (NCLX). We identified a human recessive missense SLC8B1 variant that impairs NCLX activity and is associated with severe mental retardation. On this basis, we examined the effect of deleting NCLX in mice on mitochondrial and synaptic calcium homeostasis, synaptic activity, and plasticity. Neuronal mitochondria exhibited basal calcium overload, membrane depolarization, and a reduction in the amplitude and rate of calcium influx and efflux. We observed smaller cytoplasmic calcium transients in the presynaptic terminals of NCLX-KO neurons, leading to a lower probability of release and weaker transmission. In agreement, synaptic facilitation in NCLX-KO hippocampal slices was enhanced. Importantly, deletion of NCLX abolished long term potentiation of Schaffer collateral synapses. Our results show that NCLX controls presynaptic calcium transients that are crucial for defining synaptic strength as well as short- and long-term plasticity, key elements of learning and memory processes.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Long-term Potentiation; Posttetanic Potentiation; Presynaptic Calcium; Essential Component; Na+/ca2+ Exchanger; Atp Synthesis; Mice Lacking; Ca2+ Uptake; Membrane; Release
ISSN (print) / ISBN
2399-3642
e-ISSN
2399-3642
Journal
Communications Biology
Quellenangaben
Volume: 4,
Issue: 1,
Article Number: 666
Publisher
Springer
Publishing Place
London
Non-patent literature
Publications
Reviewing status
Peer reviewed
Grants
Bert L & N Kuggie Vallee Foundation
ExNet-0041-Phase2-3 ("SyNergy-HMGU") through the Initiative and Network Fund of the Helmholtz Association
Munich Center for Systems Neurology (SyNergy EXC 2145)
ISF
BMBF through the German network for mitochondrial disorders, mitoNET
ExNet-0041-Phase2-3 ("SyNergy-HMGU") through the Initiative and Network Fund of the Helmholtz Association
Munich Center for Systems Neurology (SyNergy EXC 2145)
ISF
BMBF through the German network for mitochondrial disorders, mitoNET