Authors:

Shiv Shukla

Date Created:

Not specified

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About Paper:

Dendritic spines, tiny protrusions along the length of excitatory neurons, are the sites for synaptic contacts on dendrites. Spine morphology plays an important role in dynamic changes in strength of synaptic connections (known as synaptic plasticity) and are important in learning and memory. Dynamic remodelling of the actin cytoskeleton is the driving force behind the structural alterations of spines which occur within minutes of glutamate-activated calcium (Ca2+)-flux through NMDA receptors at the head of the spine. Actin cytoskeleton remodeling is regulated by complex interactions between actin-binding proteins (ABP) and other regulators which are downstream of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) protein signaling pathway. We aim to develop a deterministic model of the calcium signalling cascade that mediate CaMKII-dependent actin remodelling. We generated ordinary differential equations (ODE) for each species using mass-action kinetics. Upon thorough parameterization and validation by global sensitivity analysis, we explore how Ca2+ flux frequency regulates the molecular pathways that regulate actin remodelling dynamics, and consequently, dendritic spine morphology. This study compares the results from the simulation of different Ca2+ flux signals and provides conclusions and recommendations based on our observation of unique binding and activation dynamics of ABPs, particularly ADF/cofilin and profilin. Using the sensitivity analysis, we also quantify the robustness of the model output to input parameter variability.

Source:

Purdue University / 2023

Topics:

No topics listed

Co-authors:

Shiv Shukla