Stochastic shielding and edge importance for Markov chains with timescale separation

PLoS Comput Biol. 2018 Jun 18;14(6):e1006206. doi: 10.1371/journal.pcbi.1006206. eCollection 2018 Jun.

Abstract

Nerve cells produce electrical impulses ("spikes") through the coordinated opening and closing of ion channels. Markov processes with voltage-dependent transition rates capture the stochasticity of spike generation at the cost of complex, time-consuming simulations. Schmandt and Galán introduced a novel method, based on the stochastic shielding approximation, as a fast, accurate method for generating approximate sample paths with excellent first and second moment agreement to exact stochastic simulations. We previously analyzed the mathematical basis for the method's remarkable accuracy, and showed that for models with a Gaussian noise approximation, the stationary variance of the occupancy at each vertex in the ion channel state graph could be written as a sum of distinct contributions from each edge in the graph. We extend this analysis to arbitrary discrete population models with first-order kinetics. The resulting decomposition allows us to rank the "importance" of each edge's contribution to the variance of the current under stationary conditions. In most cases, transitions between open (conducting) and closed (non-conducting) states make the greatest contributions to the variance, but there are exceptions. In a 5-state model of the nicotinic acetylcholine receptor, at low agonist concentration, a pair of "hidden" transitions (between two closed states) makes a greater contribution to the variance than any of the open-closed transitions. We exhaustively investigate this "edge importance reversal" phenomenon in simplified 3-state models, and obtain an exact formula for the contribution of each edge to the variance of the open state. Two conditions contribute to reversals: the opening rate should be faster than all other rates in the system, and the closed state leading to the opening rate should be sparsely occupied. When edge importance reversal occurs, current fluctuations are dominated by a slow noise component arising from the hidden transitions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Action Potentials / physiology*
  • Algorithms
  • Computer Simulation
  • Ion Channel Gating / physiology
  • Kinetics
  • Markov Chains*
  • Membrane Potentials / physiology
  • Models, Biological
  • Models, Neurological
  • Neurons / physiology
  • Normal Distribution
  • Stochastic Processes*

Grants and funding

This project has been supported by start-up funds of the University of Nevada, Reno (DRS), a Biomedical Researcher Award of The Hartwell Foundation (RFG), and National Science Foundation grants DMS-1413770 and DEB-1654989 (PJT). This research has been supported in part by the Mathematical Biosciences Institute and the National Science Foundation under grant DMS 1440386. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.