Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation

Alexandra Stavsky,Holger Prokisch,Ivana Savic,Yael Amitai,Daniel Gitler,Cornelia Daumer-Haas,Essam A Assali,Fabiana Perocchi,Israel Sekler,Ohad Stoler,Tomer Katoshevsky,Marko Kostic,Steffen Leiz,Ilya Fleidervish

doi:10.1038/s42003-021-02114-0

Abstract

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.

Highlights

Calcium is the main driver of synaptic transmission; Neurotransmission is initiated in response to the influx of calcium ions through voltage gated calcium channels (VGCCs) in the presynaptic terminal, which is triggered by invading axonal action potentials[1,2,3]
Because these results illustrate that loss of NCLX function is linked to severe cognitive impairment, we hypothesized that disruption of calcium extrusion from the mitochondria interferes with synaptic function and may alter mechanisms of learning and memory
A decrease in the mitochondrial membrane potential combined with calcium overload at rest, as we found in NCLX knock-out (NCLX-KO) neurons, could reduce mitochondrial calcium influx and/or efflux during neuronal activity, when calcium flows into the terminal through voltage gated calcium channels[33,55,56]

Summary

Introduction

Calcium triggers synaptic vesicle fusion, determines release probability, modulates vesicle recycling, participates in long-term plasticity and regulates cellular metabolism. Our results show that NCLX controls presynaptic calcium transients that are crucial for defining synaptic strength as well as shortand long-term plasticity, key elements of learning and memory processes. The strategic localization of mitochondria in pre- and postsynaptic terminals[12,13,14] and their large capacity to sequester and release calcium ions[15,16] makes them ideally suited to regulate synaptic spatial and temporal calcium dynamics during neuronal activity. Calcium efflux is substantially slower (10-100 fold) and is mediated by the mitochondrial sodium/lithium/calcium exchanger (NCLX);[22,23], which is the main calcium extruder from mitochondria of excitable cells[24]. It has been linked to various pathologies, ranging from ischemia to neurodegenerative diseases[17,35,36]

Methods

Results

Conclusion