Mitochondria decode firing frequency and coincidences of postsynaptic APs and EPSPs

Mitochondrial metabolism is critical for brain function. However, the mechanisms linking mitochondrial energy production to neuronal activity are elusive. Using whole-cell electrical recordings from Layer 5 pyramidal neurons in cortical slices and fluorescence imaging of cytosolic, mitochondrial Ca ²⁺ indicators and endogenous NAD(P)H, we revealed ultra-fast, spike-evoked mitochondrial Ca ²⁺ transients temporally similar to cytosolic Ca ²⁺ elevations. We demonstrate that, whereas single or few spikes elicit the mitochondrial Ca ²⁺ transients throughout the cell, their amplitude is differentially regulated in distinct neuronal compartments. Thus, these signals were prominent in the soma and apical dendrites and ∼3 times smaller in basal dendrites and axons. The spike firing frequency had a subtle effect on the amplitude of the cytosolic Ca ²⁺ elevations but dramatically affected mitochondrial Ca ²⁺ transients and NAD(P)H oxidation and recovery rates. Moreover, while subthreshold EPSPs alone caused no detectable Ca ²⁺ elevation in dendritic mitochondria, the Hebbian coincidence of unitary EPSP and postsynaptic spike produced a localized, single mitochondrial Ca ²⁺ elevation. These findings suggest that neuronal mitochondria are uniquely capable of decoding firing frequency and EPSP-to-spike time intervals for tuning the metabolic rate and triggering changes in synaptic efficacy.