Decision letter | Nanoconnectomic upper bound on the variability of synaptic plasticity

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Nanoconnectomic upper bound on the variability of synaptic plasticity

Decision letter

Affiliation details

Howard Hughes Medical Institute, Salk Institute for Biological Studies, United States; Massachusetts Institute of Technology, United States; The University of Texas at Austin, United States; University of California, San Diego, United States
Sacha B Nelson, Reviewing editor, Brandeis University, United States

eLife posts the editorial decision letter and author response on a selection of the published articles (subject to the approval of the authors). An edited version of the letter sent to the authors after peer review is shown, indicating the substantive concerns or comments; minor concerns are not usually shown. Reviewers have the opportunity to discuss the decision before the letter is sent (see review process). Similarly, the author response typically shows only responses to the major concerns raised by the reviewers.

Thank you for submitting your work entitled "Nanoconnectomic Upper Bound on the Variability of Synaptic Plasticity" for peer review at eLife. Your submission has been favorably evaluated by Eve Marder (Senior editor) and three reviewers, one of whom, Sacha Nelson, is a member of our Board of Reviewing Editors. Another reviewer, Winfried Denk, also agreed to reveal his identity.

The reviewers have discussed the reviews with one another and the Reviewing editor has drafted this decision to help you prepare a revised submission.

Summary:

This elegant study makes a simple but important point. By completely reconstructing a small volume of hippocampus, the authors demonstrate that pairs of synapses between the same dendrite and axon have highly correlated sizes (and therefore from earlier work) strength. The finding, that synapses that share an axon and a dendritic branch are very similar in size, is a very important confirmation of the notion that it is the history of correlated pre- and post-synaptic activity that determines synapse size and strength. The data were carefully and creatively analyzed. The results are convincing because they have been reproduced in three animals (a very time consuming task) and because of the high p values.

Essential revisions:

1) The authors should revise the text to clarify how the analysis was carried out, and what can and what cannot be determined from the datasets studied.

Reviewer 1: "It would be surprising if synapses made by the same axon on different dendrites of the same neuron (especially if located at similar electrotonic distances) were not better correlated than synapses made onto different neurons. Perhaps this did not occur in the volume reconstructed or the volume was not large enough to assign dendrites to the same neuron. If so it would be useful to state this."

Reviewer 2: "The third paragraph of the Results reads like an orphan yet provides the estimate for how much information can be stored at hippocampal synapses. The rational and analysis should be described in the Results section in more detail which will make the data and the argument more understandable to a wider range of readers. Also a short discussion of how varying the discrimination threshold would affect the estimate would be useful."

Reviewer 3: "I am not sure I quite follow the logic of the estimate for the time or the number of action potentials the paired synapses would need to average over to achieve the degree of similarity seen. During pre-synaptic bursts the release probability could go quite high, removing the noise due to the stochastic release seen during single APs.

I found myself confused by the use of "dendritic branch" and "dendrite". If might be better to use "dendritic branch" exclusively when talking about the data in the paper since the small size of the data set does not allow the determination of whether two branches belong to the same cell or not.

I am also somewhat puzzled by the statement "Difference in volume between pairs of spines is not correlated with separation distance", which heads the caption of Figure 14. First of all, not observing a correlation does not imply that there isn't any. At best an upper bound could be given for the actual correlation, but for small numbers of observation that estimate would be rather soft. Furthermore, to me, it looks like there is a trend towards greater variability as the distance increases, which would indicate the involvement of a diffusible signal in the size determination.

Ordering the spines by size before correlation analysis is inappropriate since it induces a correlation between them in the sense that knowing something about spine 1 tells me something about spine 2. Please randomize and redo the analysis.”

2) The authors should strive to make the presentation more concise.

Reviewer 1: "My only major suggestion for improving the paper is to make it more concise. Many of the figures are largely redundant (two are not cited in the text)."

Reviewer 3: "The paper could benefit from pruning some of the figures."

Please note, that if you feel strongly that you want to keep some of the images that the reviewers questioned, they should be included as Supplements to the Figures they "duplicate".

DOI: http://dx.doi.org/10.7554/eLife.10778.020