Neuronal calcium wave propagation varies with changes in endoplasmic reticulum parameters: a computer model

Neural Comput. 2015 Apr;27(4):898-924. doi: 10.1162/NECO_a_00712. Epub 2015 Mar 3.


Calcium (Ca²⁺) waves provide a complement to neuronal electrical signaling, forming a key part of a neuron's second messenger system. We developed a reaction-diffusion model of an apical dendrite with diffusible inositol triphosphate (IP₃), diffusible Ca²⁺, IP₃ receptors (IP₃Rs), endoplasmic reticulum (ER) Ca²⁺ leak, and ER pump (SERCA) on ER. Ca²⁺ is released from ER stores via IP₃Rs upon binding of IP₃ and Ca²⁺. This results in Ca²⁺-induced-Ca²⁺-release (CICR) and increases Ca²⁺ spread. At least two modes of Ca²⁺ wave spread have been suggested: a continuous mode based on presumed relative homogeneity of ER within the cell and a pseudo-saltatory model where Ca²⁺ regeneration occurs at discrete points with diffusion between them. We compared the effects of three patterns of hypothesized IP₃R distribution: (1) continuous homogeneous ER, (2) hotspots with increased IP₃R density (IP₃R hotspots), and (3) areas of increased ER density (ER stacks). All three modes produced Ca²⁺ waves with velocities similar to those measured in vitro (approximately 50-90 μm /sec). Continuous ER showed high sensitivity to IP₃R density increases, with time to onset reduced and speed increased. Increases in SERCA density resulted in opposite effects. The measures were sensitive to changes in density and spacing of IP₃R hotspots and stacks. Increasing the apparent diffusion coefficient of Ca²⁺ substantially increased wave speed. An extended electrochemical model, including voltage-gated calcium channels and AMPA synapses, demonstrated that membrane priming via AMPA stimulation enhances subsequent Ca²⁺ wave amplitude and duration. Our modeling suggests that pharmacological targeting of IP₃Rs and SERCA could allow modulation of Ca²⁺ wave propagation in diseases where Ca²⁺ dysregulation has been implicated.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium Channels, N-Type / physiology
  • Calcium Signaling / physiology*
  • Computer Simulation*
  • Endoplasmic Reticulum / physiology*
  • Models, Neurological*
  • Neurons / ultrastructure*
  • Potassium Channels
  • Receptors, AMPA / metabolism
  • Sodium Channels / metabolism


  • Calcium Channels, N-Type
  • Potassium Channels
  • Receptors, AMPA
  • Sodium Channels