Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation
| Autor: | Tomer Katoshevsky, Fabiana Perocchi, Daniel Gitler, Essam A. Assali, Steffen Leiz, Ohad Stoler, Marko Kostic, Yael Amitai, Ilya A. Fleidervish, Ivana Savic, Israel Sekler, Alexandra Stavsky, Holger Prokisch, Cornelia Daumer-Haas |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
QH301-705.5 Neural facilitation Medicine (miscellaneous) chemistry.chemical_element Neurotransmission Calcium Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Cellular neuroscience medicine Synaptic transmission Biology (General) Calcium signaling Calcium metabolism Calcium signalling Long-term potentiation Mitochondria Cell biology 030104 developmental biology medicine.anatomical_structure chemistry Schaffer collateral General Agricultural and Biological Sciences 030217 neurology & neurosurgery |
| Zdroj: | Communications Biology, Vol 4, Iss 1, Pp 1-14 (2021) Comm. Biol. 4:666 (2021) Communications Biology |
| ISSN: | 2399-3642 |
| Popis: | 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. Stavsky et al. examined the effects of deleting the mitochondrial sodium/lithium/calcium exchanger, NCLX, on mitochondrial and synaptic calcium homeostasis, synaptic activity, and plasticity in mice. Having identified a human mutation that impairs NCLX activity and is associated with mental retardation, they show that NCLX is crucial for defining synaptic strength and plasticity, which are pivotal elements of learning and memory. |
| Databáze: | OpenAIRE |
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