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    Bioinformatics, Computational and Systems Biology

    Computational Modeling of the Role of Ca2+ Flux Frequency Decoding by Calmodulin and CaMKII on Actin Polymerization Dynamics and Dendritic Spine Morphology

    (A-31) Computational Modeling of the Role of Ca2+ Flux Frequency Decoding by Calmodulin and CaMKII on Actin Polymerization Dynamics and Dendritic Spine Morphology

    Thursday, October 12, 2023
    9:30 AM – 10:30 AM PDT
    Location: Exhibit Hall - Row A - Poster # 31

      Presenting Author(s)

    • Shiv S. Shukla

      Undergraduate Student
      Purdue University
      West Lafayette, Indiana, United States

      • Co-Author(s)

    • Barrett F. Davis

      PhD Student
      Purdue University, Indiana, United States

      • Primary Investigator(s)

    • TK

      Tamara Kinzer-Ursem

      Professor
      Purdue University, United States

    Introduction::
    The morphology of neuronal synapses plays an important role in the plasticity of these synapses and are important in learning and memory. In neurodegenerative diseases exhibiting cognitive impairments such as Alzheimer’s disease (AD), which currently affects 1 in every 9 people, alterations in shape and number of dendritic spines are observed before eventual neuronal death. 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 multiple interactions between actin-binding proteins (ABP) and other regulators which are downstream of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) protein signaling pathway. However, the regulation of ABPs under different physiological conditions remains poorly understood.


    Materials and Methods::
    A deterministic model of the calcium signalling cascade that mediates CaMKII-dependent actin remodelling was developed using mass-action kinetics. To determine the model inputs that contribute the most to variation in model output, global sensitivity analysis was performed using Sobol’s method. This allowed us to quantify the first, second and total order interactions between biochemical species and the kinetics parameters governing these reactions. We compared the results from the simulation of different Ca2+-flux signals. The differential effects of two protein pathways (Rac and Rho) were investigated.


    Results, Conclusions, and Discussions::

    We expect to see that each pathway differentially activates or inactivates the ABPs consequently leading to downstream differences in actin polymerization dynamics. This will enable us to understand which pathways are critical regulators on dendritic spine morphology. Our analysis offers a better understanding of actin binding protein regulation in response to Ca2+-flux, shedding light on the molecular mechanisms of learning and memory and how dysregulation can arise in the pathologies associated with of cognitive impairments in neurodegenerative diseases.


     



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