Role of Na+/K+ pump in rhythm generation of a motor control circuit

Georgia State University, Atlanta GA

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Abstract

Robust bursting activity of neurons is critical for motor pattern generation and brain rhythms, and depends on a subtle balance of inward and outward currents. A little recognized contributor is the outward current originating with the Na+/K+ pump. The pump not only maintains the Na+ and K+ gradients across neuronal membranes, but produces an inherent outward current, which is dynamic because the pump is regulated by the internal Na+ concentration up to saturation. As yet the actual dynamical mechanisms by which pump current contributes to bursting activity are not well understood. Much work on the functional contribution of pump current to rhythmic motor activity has emphasized a time scale of a minute affecting bouts of bursting, but our recent work shows that the pump can influence individual burst in a rhythmic motor system (time scale of seconds). The interplay of inward Na+ currents and outward Na+/K+ pump current can afford rich dynamics to bursting networks. We will study how pump dynamics contribute to bursting activity in the leech heartbeat central pattern generator (CPG) because of the unique accessibility of the neurons and the wealth of experimental and modeling analyses of the system. The premise of this proposal is that the Na+/K+ pump contributes to the dynamics of neurons on the time scale of the period of their rhythmic bursting activity (6-10 s). In the leech heartbeat CPG, the basic building blocks are half-center oscillators (HCOs), which are pairs of mutually inhibitory HN interneurons producing alternating bursting activity. Our central hypothesis is that the Na+/K+ pump current through its interaction with inward currents supports robust bursting in both individual neurons and in HCO networks that allows for control of burst characteristics through modulation. To test this hypothesis we must be able to directly control both the pump current and the currents with which it interacts. A critical barrier has been the lack of experimental tools to manipulate these currents independently and together. We are developing a real-time HN model with the pump included and a dynamic clamp implementation of the pump. We will be able to introduce pump current into living HN neurons, form hybrid systems between living and model HNs, and manipulate pump parameters on the fly to investigate the role of Na+/K+ pump in rhythm generation of a motor control circuit. Aim 1. Develop a real-time hybrid system (real time model and dynamic clamp implementation). Aim 2. Investigate how burst initiation, maintenance, and termination mechanisms interact to control burst duration, interburst interval, and spike frequency.