Robust bursting dynamics based on the interaction of persistent Na and Na/K pump currents: a dynamic clamp approach.

Abstract

Life-supporting rhythmic motor functions like heart-beating in invertebrates and breathing in vertebrates require an indefatigable generation of a robust rhythm by specialized oscillatory circuits, Central Pattern Generators (CPGs). These CPGs should be sufficiently flexible to adjust to environmental changes and behavioral goals. Continuous self-sustained operation of bursting neurons requires intracellular Na+ concentration to remain in a functional range and to have checks and balances of the Na+ fluxes met on a cycle-to-cycle basis during bursting. We hypothesize that at a high excitability state, the interaction of the Na+/K+ pump current, Ipump and persistent Na+ current, INaP, produces a mechanism supporting functional bursting. INaP is a low voltage-activated inward current that initiates and supports the bursting phase. This current does not inactivate and is a significant source of Na+ influx. Ipump is an outward current activated by [Na+]i and is the major source of Na+ efflux. Both currents are active and counteract each other between and during bursts. We apply a combination of electrophysiology, computational modeling, and dynamic clamp to investigate the role of Ipump and INaP in the leech heartbeat CPG interneurons (HN neurons). Applying dynamic clamp to introduce additional Ipump and INaP into the dynamics of living synaptically isolated HN neurons in real-time, we show that their joint increase produces transition into a new bursting regime characterized by higher spike frequency and larger amplitude of the membrane potential oscillations. Further increase of Ipump speeds up this rhythm by shortening burst duration and interburst interval.Significance statementCentral Pattern Generators (CPGs) are neuronal networks that control rhythmic motor functions such as breathing and walking. Synaptic and membrane properties enable participating neurons to generate functional bursting patterns; intracellular Na+ concentration reflects the intensity of the spiking activity during bursts and regulates the Na+/K+ pump current playing a critical role in sculpting these patterns by providing negative feedback in response to excitation. Here, we show that the dynamic interaction of Na+/K+ pump current with persistent Na+ current offers a mechanism for the generation of a robust and flexible pattern of bursting activity. We provide physiological data and present a simple model that explains the underlying dynamics of the oscillatory mechanism.