A Model of Induction of Cerebellar Long-Term Depression Including RKIP Inactivation of Raf and MEK

Abstract

We report an updated stochastic model of cerebellar Long Term Depression (LTD) with improved realism. Firstly, we verify experimentally that dissociation of Raf kinase inhibitor protein (RKIP) from Mitogen-activated protein kinase kinase (MEK) is required for cerebellar LTD and add this interaction to an earlier published model, along with the known requirement of dissociation of RKIP from Raf kinase. We update Ca2+ dynamics as a constant-rate influx, which captures experimental input profiles accurately. We improve α-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor interactions by adding phosphorylation and dephosphorylation of AMPA receptors when bound to glutamate receptor interacting protein (GRIP). The updated model is tuned to reproduce experimental Ca2+ peak vs. LTD amplitude curves at four different Ca2+ pulse durations as closely as possible. We find that the updated model is generally more robust with these changes, yet we still observe some sensitivity of LTD induction to copy number of the key signaling molecule Protein kinase C (PKC). We predict natural variability in this number by stochastic diffusion may influence the probabilistic LTD response to Ca2+ input in Purkinje cell spines and propose this as an extra source of stochasticity that may be important also in other signaling systems.

Challenges in Reproducibility, Replicability, and Comparability of Computational Models and Tools for Neuronal and Glial Networks, Cells, and Subcellular Structures

“…As the experimental methodology and protocols advance and various neurobiological mechanisms become better understood, the new challenges for computational modeling emerge. Few examples are molecular diffusion in synaptic clefts, dendritic spines, and in other neural compartments (Chay et al, 2016 ; Hepburn et al, 2017 ), models of neurodevelopmental phenomena (Tetzlaff et al, 2010 ; van Ooyen, 2011 ), or wider range of plasticity mechanisms explored using conventional spiking networks (Miner and Triesch, 2016 ). Finally, one can aim beyond network modeling formalism and include extracellular space, for example similarly to the approach adopted in the Cortex3D simulation tool (Zubler and Douglas, 2009 ).…”

Ca2+ Requirements for Long-Term Depression Are Frequency Sensitive in Purkinje Cells

“…Hepburn et al (2017) reported in a previous model that LTD is bistable. In our model, we clearly observed that AMPAR trajectories can be in two different states (LTD or non LTD).…”

“…We have extended a stochastic model of the LTD molecular network developed by Hepburn et al (2017) by adding a molecular model of CaMKII activation and its regulating network.…”

“…Hepburn et al (2017) recently updated a stochastic model of the LTD signaling network including a PKC-ERK-cPLA2 feedback loop, Raf-RKIP-MEK interactions, and AMPAR trafficking. We have extended this model by adding the molecular network regulating CaMKII activity and its activation (Figure 1A).…”

“…The CaMKII molecular network is based on a published model by Kawaguchi and Hirano (2013), and we have built a new four subunit CaMKII model for the activation and phosphorylation of CaMKII. We incorporated this model into the LTD molecular network developed by Hepburn et al (2017). Other LTD models including the CaMKII pathway have been developed, but they have not included the intrinsic stochasticity of biochemical interactions (Kawaguchi and Hirano, 2013).…”