Metabolic Cost of Dendritic Ca²⁺ Action Potentials in Layer 5 Pyramidal Neurons

Pyramidal neurons consume most signaling-related energy to generate action potentials (APs) and perform synaptic integration. Dendritic Ca²⁺ spike is an important integration mechanism for coupling inputs from different cortical layers. Our objective was to quantify the metabolic energy associated with the generation of Ca²⁺ APs in the dendrites. We used morphology-based computational models to simulate the dendritic Ca²⁺ spikes in layer 5 pyramidal neurons. We calculated the energy cost by converting Ca²⁺ influx into the number of ATP required to restore and maintain the homeostasis of intracellular Ca²⁺ concentrations. We quantified the effects of synaptic inputs, dendritic voltage, back-propagating Na⁺ spikes, and Ca²⁺ inactivation on Ca²⁺ spike cost. We showed that much more ATP molecules were required for reversing Ca²⁺ influx in the dendrites than for Na⁺ ion pumping in the soma during a Ca²⁺ AP. Increasing synaptic input increased the rate of dendritic depolarization and underlying Ca²⁺ influx, resulting in higher ATP consumption. Depolarizing dendritic voltage resulted in the inactivation of Ca²⁺ channels and reduced the ATP cost, while dendritic hyperpolarization increased the spike cost by de-inactivating Ca²⁺ channels. A back-propagating Na⁺ AP initiated in the soma increased Ca²⁺ spike cost in the apical dendrite when it coincided with a synaptic input within a time window of several milliseconds. Increasing Ca²⁺ inactivation rate reduced Ca²⁺ spike cost, while slowing Ca²⁺ inactivation increased the spike cost. The results revealed that the energy demand of a Ca²⁺ AP was dynamically dependent on the state of dendritic activity. These findings were important for predicting the energy budget for signaling in pyramidal cells, interpreting functional imaging data, and designing energy-efficient neuromorphic devices.