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

Area of Science:

• Neuroscience
• Computational Biology
• Biophysics

Background:

• Calcium (Ca²⁺) waves are crucial for neuronal signaling and act as a second messenger system.
• Understanding Ca²⁺ wave propagation mechanisms is vital for deciphering neuronal function and dysfunction.

Purpose of the Study:

• To model Ca²⁺ wave propagation in an apical dendrite using a reaction-diffusion framework.
• To investigate the impact of inositol triphosphate receptor (IP₃R) and endoplasmic reticulum (ER) distribution on Ca²⁺ wave dynamics.
• To explore potential therapeutic strategies targeting Ca²⁺ signaling pathways.

Main Methods:

• Developed a reaction-diffusion model incorporating diffusible inositol triphosphate (IP₃), Ca²⁺, IP₃ receptors (IP₃Rs), ER Ca²⁺ leak, and ER pump (SERCA).
• Simulated three IP₃R distribution patterns: continuous homogeneous ER, IP₃R hotspots, and ER stacks.
• Extended the model to include voltage-gated calcium channels and AMPA synapses to assess membrane potential effects.

Main Results:

• All modeled IP₃R distribution patterns generated Ca²⁺ waves with physiologically relevant velocities (50-90 μm/sec).
• Continuous ER showed sensitivity to IP₃R density, affecting wave onset time and speed; increased SERCA density had opposing effects.
• IP₃R hotspot and ER stack density/spacing influenced wave propagation; increased Ca²⁺ diffusion significantly enhanced wave speed.
• AMPA stimulation primed the membrane, enhancing subsequent Ca²⁺ wave amplitude and duration.

Conclusions:

• Neuronal Ca²⁺ wave propagation is sensitive to the spatial organization of IP₃Rs and ER.
• Pharmacological modulation of IP₃Rs and SERCA presents a potential therapeutic avenue for diseases involving Ca²⁺ dysregulation.
• The model provides insights into the interplay between electrical and Ca²⁺ signaling in neurons.