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Coupled feedback loops maintain synaptic long-term potentiation: A computational model of PKMzeta synthesis and AMPA receptor trafficking | PLOS Computational Biology

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Author summary The brain stores memories by adjusting the strengths of connections between neurons, a phenomenon known as synaptic plasticity. Different types of plasticity mechanisms have either a strengthening or a weakening effect and produce synaptic modifications that last from milliseconds to months or more. One of the most studied forms of plasticity, long-term potentiation, is a persistent increase of synaptic strength that results from stimulation and is believed to play an important role in both short-term and long-term memory. Researchers have identified many proteins and other molecules involved in long-term potentiation and formulated different hypotheses about the biochemical processes underlying its induction and maintenance. A growing number of studies support an important role for the protein PKMζ (protein kinase M Zeta) in long-term potentiation. To investigate the explanatory power of this hypothesis, we built a computational model of the proposed biochemical reactions that involve this protein and ran simulations of a number of experiments that have been reported in the literature. We find that our model is able to explain a wide range of empirical results and thus provide insights into the molecular mechanisms of memory.

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In long-term potentiation (LTP), one of the most studied types of neural plasticity, synaptic strength is persistently increased in response to stimulation. Although a number of different proteins have been implicated in the sub-cellular molecular processes underlying induction and maintenance of LTP, the precise mechanisms remain unknown. A particular challenge is to demonstrate that a proposed molecular mechanism can provide the level of stability needed to maintain memories for months or longer, in spite of the fact that many of the participating molecules have much shorter life spans. Here we present a computational model that combines simulations of several biochemical reactions that have been suggested in the LTP literature and show that the resulting system does exhibit the required stability. At the core of the model are two interlinked feedback loops of molecular reactions, one involving the atypical protein kinase PKMζ and its messenger RNA, the other involving PKMζ and GluA2-containing AMPA receptors. We demonstrate that robust bistability–stable equilibria both in the synapse’s potentiated and unpotentiated states–can arise from a set of simple molecular reactions. The model is able to account for a wide range of empirical results, including induction and maintenance of late-phase LTP, cellular memory reconsolidation and the effects of different pharmaceutical interventions.

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Messenger RNA,Synapses,Endocytosis,Enzymes,Protein synthesis,Memory,Protein translation,Enzyme inhibitors

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https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1006147

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Coupled feedback loops maintain synaptic long-term potentiation: A computational model of PKMzeta synthesis and AMPA receptor trafficking

og:description

Author summary The brain stores memories by adjusting the strengths of connections between neurons, a phenomenon known as synaptic plasticity. Different types of plasticity mechanisms have either a strengthening or a weakening effect and produce synaptic modifications that last from milliseconds to months or more. One of the most studied forms of plasticity, long-term potentiation, is a persistent increase of synaptic strength that results from stimulation and is believed to play an important role in both short-term and long-term memory. Researchers have identified many proteins and other molecules involved in long-term potentiation and formulated different hypotheses about the biochemical processes underlying its induction and maintenance. A growing number of studies support an important role for the protein PKMζ (protein kinase M Zeta) in long-term potentiation. To investigate the explanatory power of this hypothesis, we built a computational model of the proposed biochemical reactions that involve this protein and ran simulations of a number of experiments that have been reported in the literature. We find that our model is able to explain a wide range of empirical results and thus provide insights into the molecular mechanisms of memory.

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https://journals.plos.org/ploscompbiol/article/figure/image?id=10.1371/journal.pcbi.1006147.g016&size=inline

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Coupled feedback loops maintain synaptic long-term potentiation: A computational model of PKMzeta synthesis and AMPA receptor trafficking

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Coupled feedback loops maintain synaptic long-term potentiation: A computational model of PKMzeta synthesis and AMPA receptor trafficking

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