Biophysical mechanisms in the mammalian respiratory oscillator re-examined with a new data-driven computational model

An autorhythmic population of excitatory neurons in the brainstem pre-Botzinger complex is a critical component of the mammalian respiratory oscillator. Two intrinsic neuronal biophysical mechanisms-a persistent sodium current (I-NaP) and a calcium-activated non-selective cationic current (I-CAN)-were proposed to individually or in combination generate cellular- and circuit-level oscillations, but their roles are debated without resolution. We re-examined these roles in a model of a synaptically connected population of excitatory neurons with I-CAN and I-NaP. This model robustly reproduces experimental data showing that rhythm generation can be independent of I-CAN activation, which determines population activity amplitude. This occurs when I-CAN is primarily activated by neuronal calcium fluxes driven by synaptic mechanisms. Rhythm depends critically on I-NaP in a subpopulation forming the rhythmogenic kernel. The model explains how the rhythm and amplitude of respiratory oscillations involve distinct biophysical mechanisms.