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

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) kinasedependent 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.

Lipid signaling in cytosolic phospholipase A 2 α–cyclooxygenase-2 cascade mediates cerebellar long-term depression and motor learning

“…1, blue arrows) (17-19). Hence, after the Ca 2+ surge, self-regeneration may develop by positive feedback through this closed loop, leading to a rapid, intense activation of PKCα that switches the status of PF-AMPARs from a basal state to the persistently depressed state for LTD (8,20).…”

Raf Kinase Inhibitory Protein (RKIP): Functional Pleiotropy in the Mammalian Brain

“…39 Previous work indicated that activated MAPK goes on to phosphorylate phospholipase A2 (PLA2), which produces arachidonic acid (AA) to further activate PKC and complete the positive feedback loop. [41][42][43] Similar to the study by Antoun et al, the work of Yamamoto et al focused solely on the PKC-MAPK signaling axis, and did not address the potential contribution of RKIP to other signaling pathways that participate in cerebellar LTD induction. For instance, GRK2 has been shown to desensitize the metabotropic glutamate receptor, mGluR1, a key player in cerebellar LTD. 44,45 Future studies should address whether RKIP-dependent modulation of GRK2 activity is working in concert with the PKC-MAPK positive feedback mechanism to drive LTD induction.…”

From ‘Understanding the Brain by Creating the Brain’ towards manipulative neuroscience

“…However, a considerable number of studies have reported violations of these three requirements under some experimental conditions; consequently, LTD has been questioned several times as the elementary process of cerebellar supervised learning (Llinas et al 1997) and has been postulated for other functions, such as the normalization of total synaptic efficacies on a single Purkinje cell (De Schutter 1995). The kinetic simulation model of LTD signal transduction pathways in a Purkinje cell dendritic spine (figure 5), which has been developed in a series of publications from our group (Kuroda et al 2001;Doi et al 2005;Ogasawara et al 2007) and was recently supported experimentally (Tanaka et al 2007), provided a coherent perspective on these confusing experimental data and competing theoretical hypotheses, and it is introduced in this section.…”

“…In the model proposed by Kuroda et al (2001), the large Ca 2C increase, which is caused by the conjunctive parallel fibre input and the delayed climbing fibre input, induces the activation of linear cascades of phosphorylation of protein kinase C (PKC) followed by phosphorylation and then internalization of AMPA-R, which explains the early phase of LTD up to approximately 10 minutes. On the other hand, the intermediate phase of LTD up to several tens of minutes is mediated by a mitogen-activated protein (MAP) kinase-dependent positive-feedback loop, which consists of PKC, Raf, MAP/extracellular signal-regulated kinase (MEK), MAP kinase, cytosolic phosopholipase A 2 (PLA 2 ), arachidonic acid (AA) and back to PKC (the magenta loop in the middle of figure 5).…”

“…In the NO model (one-third on left-hand side of figure 5), which was first proposed by Kuroda et al (2001) and then extensively studied in combination with electrical properties of dendrites by Ogasawara et al (2007), NO activates soluble guanylyl cyclase (sGC), and the activated sGC catalyses the conversion of GTP into cGMP, which activates cGMP-dependent protein kinase (PKG). PKG phosphorylates its substrate, G-substrate and the phosphorylated G-substrate preferentially inhibits protein phosphatase 2A (PP2A).…”