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Open Access Highly Accessed Research article

The protein kinase Mζ network as a bistable switch to store neuronal memory

Hideaki Ogasawara123* and Mitsuo Kawato2

Author Affiliations

1 National Institute of Information and Communications Technology, 2-2-2, Hikaridai, Seika, Kyoto 619-0288, Japan

2 ATR Brain Information Communication Research Laboratory Group, 2-2-2, Hikaridai, Seika, Kyoto 619-0288, Japan

3 Current Address: Pharmacovigilance Department, Astellas Pharma Inc., 3-17-1, Hasune, Itabashi, Tokyo 174-8612, Japan

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BMC Systems Biology 2010, 4:181  doi:10.1186/1752-0509-4-181

Published: 31 December 2010

Abstract

Background

Protein kinase Mζ (PKMζ), the brain-specific, atypical protein kinase C isoform, plays a key role in long-term maintenance of memory. This molecule is essential for long-term potentiation of the neuron and various modalities of learning such as spatial memory and fear conditioning. It is unknown, however, how PKMζ stores information for long periods of time despite molecular turnover.

Results

We hypothesized that PKMζ forms a bistable switch because it appears to constitute a positive feedback loop (PKMζ induces its local synthesis) part of which is ultrasensitive (PKMζ stimulates its synthesis through dual pathways). To examine this hypothesis, we modeled the biochemical network of PKMζ with realistic kinetic parameters. Bifurcation analyses of the model showed that the system maintains either the up state or the down state according to previous inputs. Furthermore, the model was able to reproduce a variety of previous experimental results regarding synaptic plasticity and learning, which suggested that it captures the essential mechanism for neuronal memory. We proposed in vitro and in vivo experiments that would critically examine the validity of the model and illuminate the pivotal role of PKMζ in synaptic plasticity and learning.

Conclusions

This study revealed bistability of the PKMζ network and supported its pivotal role in long-term storage of memory.