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Inhibition of Semaphorin3A Promotes Ocular Dominance Plasticity in the Adult Rat Visual Cortex

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Abstract

Perineuronal nets (PNNs) are condensed structures in the extracellular matrix that mainly surround GABA-ergic parvalbumin-positive interneurons in the adult brain. Previous studies revealed a parallel between PNN formation and the closure of the critical period. Moreover, ocular dominance plasticity is enhanced in response to PNN manipulations in adult animals. However, the mechanisms through which perineuronal nets modulate plasticity are still poorly understood. Recent work indicated that perineuronal nets may convey molecular signals by binding and storing proteins with important roles in cellular communication. Here we report that semaphorin3A (Sema3A), a chemorepulsive axon guidance cue known to bind to important perineuronal net components, is necessary to dampen ocular dominance plasticity in adult rats. First, we showed that the accumulation of Sema3A in PNNs in the visual cortex correlates with critical period closure, following the same time course of perineuronal nets maturation. Second, the accumulation of Sema3A in perineuronal nets was significantly reduced by rearing animals in the dark in the absence of any visual experience. Finally, we developed and characterized a tool to interfere with Sema3A signaling by means of AAV-mediated expression of receptor bodies, soluble proteins formed by the extracellular domain of the endogenous Sema3A receptor (neuropilin1) fused to a human IgG Fc fragment. By using this tool to antagonize Sema3A signaling in the adult rat visual cortex, we found that the specific inhibition of Sema3A promoted ocular dominance plasticity. Thus, Sema3A accumulates in perineuronal nets in an experience-dependent manner and its presence in the mature visual cortex inhibits plasticity.

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Acknowledgments

The first four authors (marked with an asterisk) equally contributed to this study.

Funding

This work was supported by the EU 7th Framework program (FP7) Marie Curie actions (AxRegen) 2008–2012 to JV.

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Authors and Affiliations

  1. Institute of Neuroscience, National Research Council CNR, Via Moruzzi, 1, 56124, Pisa, Italy

    Elena Maria Boggio, Laura Baroncelli & Tommaso Pizzorusso

  2. Laboratory for Regeneration of Sensorimotor Systems, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Science, Meibergdreef 47, 1105 BA, Amsterdam, The Netherlands

    Erich M. Ehlert, Elizabeth B. Moloney, Fred De Winter, Vasilis Mecollari & Joost Verhaagen

  3. BIO@SNS lab, Scuola Normale Superiore via Moruzzi, 1, 56124, Pisa, Italy

    Leonardo Lupori & Tommaso Pizzorusso

  4. Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY, 40536, USA

    Craig W. Vander Kooi

  5. Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, 56128, Pisa, Italy

    Laura Baroncelli

  6. UniQure, Meibergdreef 61, 1105 BA, Amsterdam, The Netherlands

    Bas Blits

  7. John van Geest Centre for Brain Repair, Robinson Way, Cambridge, CB2 0PY, UK

    James W. Fawcett

  8. Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, De Boelelaan 20 1085, 1081 HV, Amsterdam, The Netherlands

    Joost Verhaagen

  9. Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA University of Florence, Area San Salvi – Pad. 26, 50135, Florence, Italy

    Tommaso Pizzorusso

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  1. Elena Maria Boggio
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  2. Erich M. Ehlert
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  3. Leonardo Lupori
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  4. Elizabeth B. Moloney
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  5. Fred De Winter
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  9. Bas Blits
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  12. Tommaso Pizzorusso
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Correspondence to Tommaso Pizzorusso.

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All experiments were carried out in accordance with the European Communities Council Directive of November 24, 1986 (86/609/EEC) and were approved by the Italian Ministry of Health (authorization number 1152/2016-PR).

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Elena Maria Boggio, Erich M. Ehlert, Leonardo Lupori and Elizabeth B. Moloney contributed equally to this work.

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Boggio, E.M., Ehlert, E.M., Lupori, L. et al. Inhibition of Semaphorin3A Promotes Ocular Dominance Plasticity in the Adult Rat Visual Cortex. Mol Neurobiol 56, 5987–5997 (2019). https://doi.org/10.1007/s12035-019-1499-0

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