Abstract
Calcium () 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 (
), diffusible
,
receptors (
s), endoplasmic reticulum (ER)
leak, and ER pump (SERCA) on ER.
is released from ER stores via
s upon binding of
and
. This results in
-induced-
-release (CICR) and increases
spread. At least two modes of
wave spread have been suggested: a continuous mode based on presumed relative homogeneity of ER within the cell and a pseudo-saltatory model where
regeneration occurs at discrete points with diffusion between them. We compared the effects of three patterns of hypothesized
distribution: (1) continuous homogeneous ER, (2) hotspots with increased
density (
hotspots), and (3) areas of increased ER density (ER stacks). All three modes produced
waves with velocities similar to those measured in vitro (approximately 50–90
m /sec). Continuous ER showed high sensitivity to
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
hotspots and stacks. Increasing the apparent diffusion coefficient of
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
wave amplitude and duration. Our modeling suggests that pharmacological targeting of
s and SERCA could allow modulation of
wave propagation in diseases where
dysregulation has been implicated.