Frequency- and spike-timing-dependent mitochondrial Ca2+ signaling regulates the metabolic rate and synaptic efficacy in cortical neurons.

Alexandra Stavsky,Ohad Stoler,Yana Khrapunsky,Daniel Gitler,Ilya Fleidervish,Israel Melamed,Israel Sekler,Grace Stutzmann

doi:10.7554/elife.74606

Abstract

Mitochondrial activity is crucial for the plasticity of central synapses, but how the firing pattern of pre- and postsynaptic neurons affects the mitochondria remains elusive. We recorded changes in the fluorescence of cytosolic and mitochondrial Ca2+ indicators in cell bodies, axons, and dendrites of cortical pyramidal neurons in mouse brain slices while evoking pre- and postsynaptic spikes. Postsynaptic spike firing elicited fast mitochondrial Ca2+ responses that were about threefold larger in the somas and apical dendrites than in basal dendrites and axons. The amplitude of these responses and metabolic activity were extremely sensitive to the firing frequency. Furthermore, while an EPSP alone caused no detectable Ca2+ elevation in the dendritic mitochondria, the coincidence of EPSP with a backpropagating spike produced prominent, highly localized mitochondrial Ca2+ hotspots. Our results indicate that mitochondria decode the spike firing frequency and the Hebbian temporal coincidences into the Ca2+ signals, which are further translated into the metabolic output and most probably lead to long-term changes in synaptic efficacy.

Highlights

For the neuronal circuit to function properly, the energy demand in all compartments of the individual neurons needs to be precisely matched by local, primarily mitochondrial (Celsi et al, 2009; Rangaraju et al, 2019), ATP production
To improve the temporal resolution of the optical signals, dynamic fluorescence measurements were obtained from the smaller regions of interest in soma, axon, and dendrites
We extended our analysis by measuring the cytosolic and mitochondrial Ca2+ signals elicited by 20 unpaired action potentials (APs) and APs paired with EPSP

Summary

Introduction

For the neuronal circuit to function properly, the energy demand in all compartments of the individual neurons needs to be precisely matched by local, primarily mitochondrial (Celsi et al, 2009; Rangaraju et al, 2019), ATP production. During periods of enhanced neuronal activity, mitochondria accelerate ATP production by allowing the cytosolic Ca2+. Elevations to propagate into the mitochondrial matrix (Ashrafi et al, 2020; Diaz-Garcia et al, 2021). The mitochondrial Ca2+ elevation increases ATP production by activating at least three Krebs cycle enzymes (De Stefani et al, 2016; Wescott et al, 2019). When Ca2+ signaling is disrupted, mitochondria in presynaptic terminals fail to maintain the stable ATP concentration during enhanced activity periods (Ashrafi et al, 2020; Giorgio et al, 2013; Glancy and Balaban, 2012). The link between the distinctive types of the neuronal electrical activity, mitochondrial Ca2+ signaling and metabolism in other neuronal compartments is poorly understood,

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