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

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

doi:10.7554/elife.74606

Cited by 16 publications

(20 citation statements)

References 44 publications

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“…Elevations in mitochondrial Ca 2+ were largely absent during lowfrequency action potential firing, but rapidly became larger and more prolonged in response to high-frequency trains or physiologically relevant bursting patterns. This relationship was also described in another recent study on cortical pyramidal neurons in brain slices 79 . As the in vitro K d of mRGECO is similar (0.48 µM) to the resting mitochondrial Ca 2+ concentration 48,80 , the lack of responsiveness at low activity levels likely reflects a true absence of Ca 2+ uptake rather than unresponsiveness of the sensor.…”

Section: Discussionsupporting

confidence: 76%

“…8). This dual role of mitochondrial Ca 2+ uptake in the somatodendritic compartment could shape action potential output as well as synaptic integration and plasticity in the dendrites, where mitochondrial Ca 2+ uptake was recently shown to occur during coincident pre-and post-synaptic activity 79 . We expect that MCU activation in pyramidal neurons influences sensorimotor processing and other cognitive functions, as in vivo recordings of cortical and hippocampal pyramidal neurons have shown firing intensities within the range of our experimental stimuli 39,62,111,112 .…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial Ca2+ uptake by the MCU facilitates pyramidal neuron excitability and metabolism during action potential firing

Groten

MacVicar

2022

Commun Biol

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Neuronal activation is fundamental to information processing by the brain and requires mitochondrial energy metabolism. Mitochondrial Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU) has long been implicated in the control of energy metabolism and intracellular Ca2+ signalling, but its importance to neuronal function in the brain remains unclear. Here, we used in situ electrophysiology and two-photon imaging of mitochondrial Ca2+, cytosolic Ca2+, and NAD(P)H to test the relevance of MCU activation to pyramidal neuron Ca2+ signalling and energy metabolism during action potential firing. We demonstrate that mitochondrial Ca2+ uptake by the MCU is tuned to enhanced firing rate and the strength of this relationship varied between neurons of discrete brain regions. MCU activation promoted electron transport chain activity and chemical reduction of NAD+ to NADH. Moreover, Ca2+ buffering by mitochondria attenuated cytosolic Ca2+ signals and thereby reduced the coupling between activity and the slow afterhyperpolarization, a ubiquitous regulator of excitability. Collectively, we demonstrate that the MCU is engaged by accelerated spike frequency to facilitate neuronal activity through simultaneous control of energy metabolism and excitability. As such, the MCU is situated to promote brain functions associated with high frequency signalling and may represent a target for controlling excessive neuronal activity.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Mitochondrial Ca2+ uptake by the MCU facilitates pyramidal neuron excitability and metabolism during action potential firing

Groten

MacVicar

2022

Commun Biol

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“…Spike bursts are known to induce frequency- and spike-timing dependent plasticity ( 67 ). Moreover, recent findings demonstrate that spike bursts evoke pronounced mitoCa 2+ transients in soma and apical dendrites ( 68 ) and mitoCa 2+ is implicated in the induction of long-term potentiation ( 69 ). What are the mechanisms that separate the functions of burst-induced mitoCa 2+ in Hebbian vs. homeostatic plasticity?…”

Section: Discussionmentioning

confidence: 99%

IGF-1 receptor regulates upward firing rate homeostasis via the mitochondrial calcium uniporter

Katsenelson

Shapira

Abbas

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of firing rate homeostasis constitutes a fundamental property of central neural circuits. While intracellular Ca 2+ has long been hypothesized to be a feedback control signal, the molecular machinery enabling a network-wide homeostatic response remains largely unknown. We show that deletion of insulin-like growth factor-1 receptor (IGF-1R) limits firing rate homeostasis in response to inactivity, without altering the distribution of baseline firing rates. The deficient firing rate homeostatic response was due to disruption of both postsynaptic and intrinsic plasticity. At the cellular level, we detected a fraction of IGF-1Rs in mitochondria, colocalized with the mitochondrial calcium uniporter complex (MCUc). IGF-1R deletion suppressed transcription of the MCUc members and burst-evoked mitochondrial Ca 2+ (mitoCa 2+ ) by weakening mitochondria-to-cytosol Ca 2+ coupling. Overexpression of either mitochondria-targeted IGF-1R or MCUc in IGF-1R–deficient neurons was sufficient to rescue the deficits in burst-to-mitoCa 2+ coupling and firing rate homeostasis. Our findings indicate that mitochondrial IGF-1R is a key regulator of the integrated homeostatic response by tuning the reliability of burst transfer by MCUc. Based on these results, we propose that MCUc acts as a homeostatic Ca 2+ sensor. Faulty activation of MCUc may drive dysregulation of firing rate homeostasis in aging and in brain disorders associated with aberrant IGF-1R/MCUc signaling.

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“…Mitochondrial Ca 2+ uptake is known to depend on the influx of extracellular Ca 2+ (refs. 59 , 60 ), which in turn is controlled by myelination 57 . To examine a possible source for the changes in the mt-Ca 2+ , we next examined cytosolic Ca 2+ (cyt-Ca 2+ ) transients in PV + interneurons.…”

Section: Resultsmentioning

confidence: 99%

Parvalbumin basket cell myelination accumulates axonal mitochondria to internodes

et al. 2022

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Parvalbumin-expressing (PV+) basket cells are fast-spiking inhibitory interneurons that exert critical control over local circuit activity and oscillations. PV+ axons are often myelinated, but the electrical and metabolic roles of interneuron myelination remain poorly understood. Here, we developed viral constructs allowing cell type-specific investigation of mitochondria with genetically encoded fluorescent probes. Single-cell reconstructions revealed that mitochondria selectively cluster to myelinated segments of PV+ basket cells, confirmed by analyses of a high-resolution electron microscopy dataset. In contrast to the increased mitochondrial densities in excitatory axons cuprizone-induced demyelination abolished mitochondrial clustering in PV+ axons. Furthermore, with genetic deletion of myelin basic protein the mitochondrial clustering was still observed at internodes wrapped by noncompacted myelin, indicating that compaction is dispensable. Finally, two-photon imaging of action potential-evoked calcium (Ca2+) responses showed that interneuron myelination attenuates both the cytosolic and mitochondrial Ca2+ transients. These findings suggest that oligodendrocyte ensheathment of PV+ axons assembles mitochondria to branch selectively fine-tune metabolic demands.

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

Cited by 16 publications

References 44 publications

Mitochondrial Ca2+ uptake by the MCU facilitates pyramidal neuron excitability and metabolism during action potential firing

Mitochondrial Ca2+ uptake by the MCU facilitates pyramidal neuron excitability and metabolism during action potential firing

IGF-1 receptor regulates upward firing rate homeostasis via the mitochondrial calcium uniporter

Parvalbumin basket cell myelination accumulates axonal mitochondria to internodes

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