Sodium and calcium mechanisms of rhythmic bursting in excitatory neural networks of the pre‐Bötzinger complex: a computational modelling study

Abstract The neural mechanisms generating rhythmic bursting activity in the mammalian brainstem, particularly in the pre‐ B ötzinger complex (pre‐ B öt C ), which is involved in respiratory rhythm generation, and in the spinal cord (e.g. locomotor rhythmic activity) that persist after blockade of synaptic inhibition remain poorly understood. Experimental studies in rodent medullary slices containing the pre‐ B öt C identified two mechanisms that could potentially contribute to the generation of rhythmic bursting: one based on the persistent N a + current ( I NaP ), and the other involving the voltage‐gated C a 2+ current ( I Ca ) and the C a 2+ ‐activated nonspecific cation current ( I CAN ), activated by intracellular C a 2+ accumulated from extracellular and intracellular sources. However, the involvement and relative roles of these mechanisms in rhythmic bursting are still under debate. In this theoretical/modelling study, we investigated N a + ‐dependent and C a 2+ ‐dependent bursting generated in single cells and heterogeneous populations of synaptically interconnected excitatory neurons with I NaP and I Ca randomly distributed within populations. We analysed the possible roles of network connections, ionotropic and metabotropic synaptic mechanisms, intracellular C a 2+ release, and the N a + / K + pump in rhythmic bursting generated under different conditions. We show that a heterogeneous population of excitatory neurons can operate in different oscillatory regimes with bursting dependent on I NaP and/or I CAN , or independent of both. We demonstrate that the operating bursting mechanism may depend on neuronal excitation, synaptic interactions within the network, and the relative expression of particular ionic currents. The existence of multiple oscillatory regimes and their state dependence demonstrated in our models may explain different rhythmic activities observed in the pre‐BötC and other brainstem/spinal cord circuits under different experimental conditions.