Exploration of Signal Transduction Pathways in Cerebellar Long-Term Depression by Kinetic Simulation

Shinya Kuroda^{1, 2}, Nicolas Schweighofer¹, and Mitsuo Kawato^{1, 3
1} Kawato Dynamic Brain Project, ERATO, Japan Science and Technology, Kyoto 619-0288, Japan, ² Division of Signal Transduction, Nara Institute of Science and Technology, Ikoma 630-0101, Japan, and ³ ATR, Kyoto 619-0288, Japan

Correspondence should be addressed to Shinya Kuroda, now at Undergraduate Program for Bioinformatics and Systems Biology, Graduate School of Information Science and Technology, University of Tokyo.
E-mail:skuroda@is.s.u-tokyo.ac.jp, webpage: www.kurodalab.org.

Full text article[PDF file:0.87MB]

Abstract

Because multiple molecular signal transduction pathways regulate cerebellar long-term depression (LTD), which is thought to be a possible molecular and cellular basis of cerebellar learning, the systematic relationship between cerebellar LTD and the currently known signal transduction pathways remains obscure. To address this issue, we built a new diagram of signal transduction pathways and developed a computational model of kinetic simulation for the phosphorylation of AMPA receptors, known as a key step for expressing cerebellar LTD. The phosphorylation of AMPA receptors in this model consists of an initial phase and an intermediate phase. We show that the initial phase is mediated by the activation of linear cascades of protein kinase C (PKC), whereas the intermediate phase is mediated by a mitogen-activated protein (MAP) kinase-dependent positive feedback loop pathway that is responsible for the transition from the transient phosphorylation of the AMPA receptors to the stable phosphorylation of the AMPA receptors. These phases are dually regulated by the PKC and protein phosphatase pathways. Both phases also require nitric oxide (NO), although NO per se does not show any ability to induce LTD; this is consistent with a permissive role as reported experimentally (Lev-Ram et al., 1997). Therefore, the kinetic simulation is a powerful tool for understanding and exploring the behaviors of complex signal transduction pathways involved in cerebellar LTD.

Supplementary Information

Kinetic parameters

Model

Simulation Environment: GENESIS, Kinetikit
the model script [gzip-compressed, 129 kb]

Simulation Demo

README for simulation demo
Minimum set of simulation demo and GENESIS/kinetikit [tar.gz file, 1.24 MB]
Extraced files of the minimum set