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

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.

Automated summary

Mitochondrial activity plays a crucial role in synaptic plasticity, and the firing pattern of pre- and postsynaptic neurons affects mitochondrial function. Our study revealed that postsynaptic spike firing induces rapid mitochondrial Ca2+ responses, with larger responses observed in cell bodies and apical dendrites. Additionally, the coincidence of an EPSP with a backpropagating spike generated prominent mitochondrial Ca2+ hotspots. These findings suggest that mitochondria decode spike firing patterns into Ca2+ signals, which in turn influence metabolic output and may lead to long-term changes in synaptic efficacy.