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Persistent cortical plasticity by upregulation of chondroitin 6-sulfation

Nature Neuroscience volume 15, pages 414–422 (2012)Cite this article

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Abstract

Cortical plasticity is most evident during a critical period in early life, but the mechanisms that restrict plasticity after the critical period are poorly understood. We found that a developmental increase in the 4-sulfation/6-sulfation (4S/6S) ratio of chondroitin sulfate proteoglycans (CSPGs), which are components of the brain extracellular matrix, leads to the termination of the critical period for ocular dominance plasticity in the mouse visual cortex. Condensation of CSPGs into perineuronal nets that enwrapped synaptic contacts on parvalbumin-expressing interneurons was prevented by cell-autonomous overexpression of chondroitin 6-sulfation, which maintains a low 4S/6S ratio. Furthermore, the increase in the 4S/6S ratio was required for the accumulation of Otx2, a homeoprotein that activates the development of parvalbumin-expressing interneurons, and for functional maturation of the electrophysiological properties of these cells. Our results indicate that the critical period for cortical plasticity is regulated by the 4S/6S ratio of CSPGs, which determines the maturation of parvalbumin-expressing interneurons.

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Figure 1: Developmental changes of sulfation patterns of chondroitin sulfate in mouse brain.
Figure 2: Sulfation patterns of chondroitin sulfate participate in the termination of the critical period.
Figure 3: Impaired PNNs formation in C6ST-1 mice.
Figure 4: Sulfation patterns of chondroitin sulfate–dependent accumulation of Otx2 homeoprotein in parvalbumin-expressing interneurons.
Figure 5: Chondroitin 6-sulfation–enriched PNNs show a diffuse structure and are unable to tightly surround thalamocortical synaptic contacts.
Figure 6: Overexpression of C6ST-1 in parvalbumin-expressing interneurons cell-autonomously affects PNN formation.
Figure 7: Overexpression of C6ST-1 prevents the maturation of the membrane properties of fast-spiking cells.
Figure 8: Comparison of visual responsiveness in visual cortical neurons between C6ST-1 and wild-type mice.

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Acknowledgements

We thank T. Maruyama and F. Murakami for technical advises on the VEP recordings and in utero electroporation, respectively. This work was funded by a Grant-in-Aid for Scientific Research-B 21390025 (to H.K.), grants from the Scientific Research on Innovative Areas (23110003 and 23110004 to H.K. and Y.K.), and a Young Scientists grant (21890286 to S.M.) from Ministry of Education, Culture, Sports, Science & Technology, Japan.

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Authors and Affiliations

  1. Department of Biochemistry, Kobe Pharmaceutical University, Higashinada-ku, Kobe, Japan.,

    Shinji Miyata & Hiroshi Kitagawa

  2. Global Center of Excellence Program for Signal Transduction Medicine, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe, Japan.,

    Shinji Miyata & Hiroshi Kitagawa

  3. Department of Neuroscience, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

    Yukio Komatsu

  4. Division of Developmental Neurophysiology, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes for Natural Sciences, Okazaki, Japan

    Yumiko Yoshimura

  5. Laboratory for Transgenic Technology, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Choji Taya

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Contributions

S.M., Y.Y., Y.K. and H.K. designed and performed the research, analyzed the data and wrote the manuscript. S.M. and H.K. conceived the idea. C.T. produced C6ST-1 transgenic mice.

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Correspondence to Hiroshi Kitagawa.

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Miyata, S., Komatsu, Y., Yoshimura, Y. et al. Persistent cortical plasticity by upregulation of chondroitin 6-sulfation. Nat Neurosci 15, 414–422 (2012). https://doi.org/10.1038/nn.3023

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