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Research Article

SYNPLA, a method to identify synapses displaying plasticity after learning

View ORCID ProfileKim Dore, Yvonne Pao, Jose Soria Lopez, Sage Aronson, Huiqing Zhan, Sanchari Ghosh, Sabina Merrill, Anthony M. Zador, Roberto Malinow, and Justus M. Kebschull
PNAS first published January 23, 2020 https://doi.org/10.1073/pnas.1919911117
Kim Dore
aCenter for Neural Circuits and Behavior, Department of Neuroscience and Section for Neurobiology, Division of Biology, University of California San Diego, La Jolla, CA 92093;
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  • ORCID record for Kim Dore
Yvonne Pao
aCenter for Neural Circuits and Behavior, Department of Neuroscience and Section for Neurobiology, Division of Biology, University of California San Diego, La Jolla, CA 92093;
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Jose Soria Lopez
aCenter for Neural Circuits and Behavior, Department of Neuroscience and Section for Neurobiology, Division of Biology, University of California San Diego, La Jolla, CA 92093;
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Sage Aronson
aCenter for Neural Circuits and Behavior, Department of Neuroscience and Section for Neurobiology, Division of Biology, University of California San Diego, La Jolla, CA 92093;
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Huiqing Zhan
bCold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
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Sanchari Ghosh
bCold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
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Sabina Merrill
bCold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
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Anthony M. Zador
bCold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
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Roberto Malinow
aCenter for Neural Circuits and Behavior, Department of Neuroscience and Section for Neurobiology, Division of Biology, University of California San Diego, La Jolla, CA 92093;
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  • For correspondence: rmalinow@ucsd.edu justus@kebschull.me
Justus M. Kebschull
bCold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;cWatson School of Biological Sciences, Cold Spring Harbor, NY 11724;dDepartment of Biology, Stanford University, Stanford, CA 94305
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  • For correspondence: rmalinow@ucsd.edu justus@kebschull.me
  1. Contributed by Roberto Malinow, December 19, 2019 (sent for review November 13, 2019; reviewed by Joseph E. LeDoux and Mats Nilsson)

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Significance

When an animal forms a memory, synapses in specific brain pathways change their strength. Pinpointing which synapses and pathways are modulated in any given learning paradigm, however, is technically challenging and needs to be performed one candidate connection at a time. Here we present SYNPLA, a tool to quickly detect strengthened synapses in genetically or anatomically defined pathways across the brain. To do so, we exploit the temporary translocation of AMPA receptor GluA1 into newly strengthened synapses. Using an assay that can identify proteins less than 40 nm away, we label only synapses that contain both GluA1 and a presynaptic protein exogenously expressed in a specific pathway. SYNPLA thus provides a pathway- and synapse-specific screening tool for memory formation.

Abstract

Which neural circuits undergo synaptic changes when an animal learns? Although it is widely accepted that changes in synaptic strength underlie many forms of learning and memory, it remains challenging to connect changes in synaptic strength at specific neural pathways to specific behaviors and memories. Here we introduce SYNPLA (synaptic proximity ligation assay), a synapse-specific, high-throughput, and potentially brain-wide method capable of detecting circuit-specific learning-induced synaptic plasticity.

  • proximity ligation assay
  • synaptic potentiation
  • fear conditioning
  • defense conditioning
  • GluA1

Footnotes

  • ↵1To whom correspondence may be addressed. Email: rmalinow{at}ucsd.edu or justus{at}kebschull.me.
  • Author contributions: K.D., A.M.Z., R.M., and J.M.K. designed research; K.D., Y.P., S.A., H.Z., S.G., S.M., and J.M.K. performed research; K.D., Y.P., J.S.L., R.M., and J.M.K. analyzed data; and K.D., A.M.Z., R.M., and J.M.K. wrote the paper.

  • Reviewers: J.E.L., New York University; and M.N., Stockholm University.

  • The authors declare no competing interest.

  • This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1919911117/-/DCSupplemental.

Published under the PNAS license.

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SYNPLA, a method to identify synapses displaying plasticity after learning
Kim Dore, Yvonne Pao, Jose Soria Lopez, Sage Aronson, Huiqing Zhan, Sanchari Ghosh, Sabina Merrill, Anthony M. Zador, Roberto Malinow, Justus M. Kebschull
Proceedings of the National Academy of Sciences Jan 2020, 201919911; DOI: 10.1073/pnas.1919911117

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SYNPLA, a method to identify synapses displaying plasticity after learning
Kim Dore, Yvonne Pao, Jose Soria Lopez, Sage Aronson, Huiqing Zhan, Sanchari Ghosh, Sabina Merrill, Anthony M. Zador, Roberto Malinow, Justus M. Kebschull
Proceedings of the National Academy of Sciences Jan 2020, 201919911; DOI: 10.1073/pnas.1919911117
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