Temporal pattern and synergy influence activity of ERK signaling pathways during L-LTP induction

  1. Nadiatou T Miningou Zobon
  2. Joanna Jędrzejewska-Szmek
  3. Kim T Blackwell

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Abstract

Long-lasting long-term potentiation (L-LTP) is a cellular mechanism of learning and memory storage. Studies have demonstrated a requirement for extracellular signal-regulated kinase (ERK) activation in L-LTP produced by a diversity of temporal stimulation patterns. Multiple signaling pathways converge to activate ERK, with different pathways being required for different stimulation patterns. To answer whether and how different temporal patterns select different signaling pathways for ERK activation, we developed a computational model of five signaling pathways (including two novel pathways) leading to ERK activation during L-LTP induction. We show that calcium and cAMP work synergistically to activate ERK and that stimuli given with large intertrial intervals activate more ERK than shorter intervals. Furthermore, these pathways contribute to different dynamics of ERK activation. These results suggest that signaling pathways with different temporal sensitivities facilitate ERK activation to diversity of temporal patterns.

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  1. Version published to 10.7554/elife.64644 on eLife
  2. eLife

    Reviewer #3:

    This paper is primarily about modeling the ERK pathway during the induction of synaptic plasticity. This pathway has been previously modeled, and this is cited in the paper. The main addition here is the addition of the effect of SynGap which is necessary in some form of LTP. This is a very detailed study, and what it seems to primarily show is that the ERK pathway favored spaced vs. massed stimulation protocols. This is a very detailed paper, but no conceptually new ideas are presented here. The paper adds to an existing foundation, but fails to make the case that this is a very significant addition. What is the significant consequence at a higher level of these added details?

    The ERK pathway is just one component of a much larger set of pathways that control synaptic plasticity, how much do we learn from studying this pathway in isolation? Also, the paper cites the importance of this pathway to L-LTP, is it the induction phase of L-LTP? It seems so because ppRRK decays in less than an hour. How then does this pathway contribute to the maintenance of L-LTP? These processes, such as a possible upregulation of protein synthesis, are not part of this model either.

    This paper studies in detail different pathways that influence ERK activation in synapses. This is a very detailed study, but how many details do we actually know? For a detailed paper though it seems that many of the details are missing. Is there a detailed diagram of reactions, or set of equations for all these reactions? Some coefficients are named in figure 1, and this might be sufficient for a schematic description of the model in the paper, however there must be somewhere a detailed description of all reactions. How many species are there here, how many coefficients? How are coefficient values known? How many coefficients are directly estimated? The paper does carry out an extensive robustness analysis, though it is not well explained.

    What are the major takeaways from this paper, and what experiments could test this model?

    To summarize, the paper is very detailed, carefully constructed and executed, but it fails to convince that the problem it addresses is very significant, and it makes no conceptual breakthroughs.

  3. eLife

    Reviewer #2:

    Miningou and Blackwell in their manuscript titled "Temporal pattern and synergy influence activity of ERK signaling pathways during L-LTP induction" explored the contributions of upstream pathways to ERK activation during LTP. The authors expanded on their previously published LTP model to assess the influence on ERK activation of each of the upstream pathways originating from cAMP or Ca+2 activated with differing temporal patterns. This manuscript's aim is quite germane, since 1) ERK plays such a central role in learning and memory and its cellular proxy LTP; 2) the Ca+2/cAMP/PKA system is highly complex and nonlinear, with multiple feedback loops. The resulting manuscript has the potential to be impactful. The approach of using a stochastic reaction-diffusion model is state of the art and appropriate for the modeling of these subcellular events in spines. And the modeling insights are very intriguing as the authors predict that ERK activation by cAMP/PKA or Ca+2 pathways differ in their linearity, these pathways can synergize during LTP and this may involve a novel feedforward loop containing synGAP. The authors do a marvelous job placing their findings within the huge body of LTP literature.

    There are, however, a couple of points that I feel should be addressed:

    1. There needs to be additional technical detail on how the original models were expanded. The model presented here was developed by merging Jȩdrzejewska-Szmek et al., 2017 and Jain and Bhalla, 2014 models. These models were developed based on experimental data and validated with independent experimental datasets in a rigorous manner. It is not clear how the combining these two models, and the additional molecules and reactions added have affected the dynamics of ERK activation, and how comparable they are to the original experimental data used for model development in the previous modeling efforts. It is not clear if the model was reparameterized.

    2. Beyond the ERK activation traces, it would be useful for clarity sake to also include the simulated traces for the activation of the upstream molecules (PKA, RAS, RAP, etc). Given how additional changes have been made additional information should be provided to ensure that the contribution of each pathway is accurately represented.

  4. eLife

    Reviewer #1:

    This study takes on the question of the roles of the many pathways leading to ERK activation in long-term potentiation. This is an advance: few models consider more than a couple of input pathways. The authors consider two aspects: how pathways sum to give strong responses, and distinct temporal pattern selectivity. They show that both summation linearity, and pattern selectivity, are strongly governed by which pathways are engaged in driving the response.

    The model and analysis is potentially interesting, but the paper would be much strengthened if there were more convincing validation of the properties of the model by way of simulations to compare with experiments. Further, the pathways chosen are already one step into the synapse. Thus the actual combination of pathway activations would not be quite as cleanly separated if they were driven by synaptic input.

  5. Version published to 10.1101/2020.11.04.368571 on bioRxiv