Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Persistent cortical plasticity by upregulation of chondroitin 6-sulfation

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

References

  1. Wiesel, T.N. & Hubel, D.H. Single-cell responses in striate cortex of kittens deprived of vision in one eye. J. Neurophysiol. 26, 1003–1017 (1963).

    Article  CAS  Google Scholar 

  2. Hensch, T.K. Critical period plasticity in local cortical circuits. Nat. Rev. Neurosci. 6, 877–888 (2005).

    Article  CAS  Google Scholar 

  3. Gordon, J.A. & Stryker, M.P. Experience-dependent plasticity of binocular responses in the primary visual cortex of the mouse. J. Neurosci. 16, 3274–3286 (1996).

    Article  CAS  Google Scholar 

  4. Yazaki-Sugiyama, Y., Kang, S., Câteau, H., Fukai, T. & Hensch, T.K. Bidirectional plasticity in fast-spiking GABA circuits by visual experience. Nature 462, 218–221 (2009).

    Article  CAS  Google Scholar 

  5. Sugiyama, S. et al. Experience-dependent transfer of Otx2 homeoprotein into the visual cortex activates postnatal plasticity. Cell 134, 508–520 (2008).

    Article  CAS  Google Scholar 

  6. Sugahara, K. & Mikami, T. Chondroitin/dermatan sulfate in the central nervous system. Curr. Opin. Struct. Biol. 17, 536–545 (2007).

    Article  CAS  Google Scholar 

  7. Celio, M.R., Spreafico, R., De Biasi, S. & Vitellaro-Zuccarello, L. Perineuronal nets: past and present. Trends Neurosci. 21, 510–515 (1998).

    Article  CAS  Google Scholar 

  8. Galtrey, C.M. & Fawcett, J.W. The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. Brain Res. Rev. 54, 1–18 (2007).

    Article  CAS  Google Scholar 

  9. Carulli, D. et al. Composition of perineuronal nets in the adult rat cerebellum and the cellular origin of their components. J. Comp. Neurol. 494, 559–577 (2006).

    Article  CAS  Google Scholar 

  10. Pizzorusso, T. et al. Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298, 1248–1251 (2002).

    Article  CAS  Google Scholar 

  11. Bradbury, E.J. et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636–640 (2002).

    Article  CAS  Google Scholar 

  12. Gama, C.I. et al. Sulfation patterns of glycosaminoglycans encode molecular recognition and activity. Nat. Chem. Biol. 2, 467–473 (2006).

    Article  CAS  Google Scholar 

  13. Mikami, T., Yasunaga, D. & Kitagawa, H. Contactin-1 is a functional receptor for neuroregulatory chondroitin sulfate-E. J. Biol. Chem. 284, 4494–4499 (2009).

    Article  CAS  Google Scholar 

  14. Nadanaka, S., Ishida, M., Ikegami, M. & Kitagawa, H. Chondroitin 4-O-sulfotransferase-1 modulates Wnt-3a signaling through control of E disaccharide expression of chondroitin sulfate. J. Biol. Chem. 283, 27333–27343 (2008).

    Article  CAS  Google Scholar 

  15. Kitagawa, H., Tsutsumi, K., Tone, Y. & Sugahara, K. Developmental regulation of the sulfation profile of chondroitin sulfate chains in the chicken embryo brain. J. Biol. Chem. 272, 31377–31381 (1997).

    Article  CAS  Google Scholar 

  16. Properzi, F. et al. Chondroitin 6-sulphate synthesis is up-regulated in injured CNS, induced by injury-related cytokines and enhanced in axon-growth inhibitory glia. Eur. J. Neurosci. 21, 378–390 (2005).

    Article  Google Scholar 

  17. Fox, K. & Wong, R.O. A comparison of experience-dependent plasticity in the visual and somatosensory systems. Neuron 48, 465–477 (2005).

    Article  CAS  Google Scholar 

  18. Maeda, N. et al. Heterogeneity of the chondroitin sulfate portion of phosphacan/6B4 proteoglycan regulates its binding affinity for pleiotrophin/heparin binding growth-associated molecule. J. Biol. Chem. 278, 35805–35811 (2003).

    Article  CAS  Google Scholar 

  19. Frenkel, M.Y. & Bear, M.F. How monocular deprivation shifts ocular dominance in visual cortex of young mice. Neuron 44, 917–923 (2004).

    Article  CAS  Google Scholar 

  20. Godement, P., Salaün, J. & Imbert, M. Prenatal and postnatal development of retinogeniculate and retinocollicular projections in the mouse. J. Comp. Neurol. 230, 552–575 (1984).

    Article  CAS  Google Scholar 

  21. Sato, M. & Stryker, M.P. Distinctive features of adult ocular dominance plasticity. J. Neurosci. 28, 10278–10286 (2008).

    Article  CAS  Google Scholar 

  22. Härtig, W., Brauer, K. & Brückner, G. Wisteria floribunda agglutinin-labeled nets surround parvalbumin-containing neurons. Neuroreport 3, 869–872 (1992).

    Article  Google Scholar 

  23. Matthews, R.T. et al. Aggrecan glycoforms contribute to the molecular heterogeneity of perineuronal nets. J. Neurosci. 22, 7536–7547 (2002).

    Article  CAS  Google Scholar 

  24. Erisir, A. & Dreusicke, M. Quantitative morphology and postsynaptic targets of thalamocortical axons in critical period and adult ferret visual cortex. J. Comp. Neurol. 485, 11–31 (2005).

    Article  Google Scholar 

  25. Marín, O. & Rubenstein, J.L. A long, remarkable journey: tangential migration in the telencephalon. Nat. Rev. Neurosci. 2, 780–790 (2001).

    Article  Google Scholar 

  26. Tanaka, D.H. et al. Random walk behavior of migrating cortical interneurons in the marginal zone: time-lapse analysis in flat-mount cortex. J. Neurosci. 29, 1300–1311 (2009).

    Article  CAS  Google Scholar 

  27. Borrell, V., Yoshimura, Y. & Callaway, E.M. Targeted gene delivery to telencephalic inhibitory neurons by directional in utero electroporation. J. Neurosci. Methods 143, 151–158 (2005).

    Article  CAS  Google Scholar 

  28. Kawaguchi, Y. & Kondo, S. Parvalbumin, somatostatin and cholecystokinin as chemical markers for specific GABAergic interneuron types in the rat frontal cortex. J. Neurocytol. 31, 277–287 (2002).

    Article  Google Scholar 

  29. Connors, B.W. & Gutnick, M.J. Intrinsic firing patterns of diverse neocortical neurons. Trends Neurosci. 13, 99–104 (1990).

    Article  CAS  Google Scholar 

  30. Kawaguchi, Y. Physiological subgroups of nonpyramidal cells with specific morphological characteristics in layer II/III of rat frontal cortex. J. Neurosci. 15, 2638–2655 (1995).

    Article  CAS  Google Scholar 

  31. Goldberg, E.M. et al. Rapid developmental maturation of neocortical FS cell intrinsic excitability. Cereb. Cortex 21, 666–682 (2011).

    Article  Google Scholar 

  32. Hensch, T.K. et al. Local GABA circuit control of experience-dependent plasticity in developing visual cortex. Science 282, 1504–1508 (1998).

    Article  CAS  Google Scholar 

  33. Bavelier, D., Levi, D.M., Li, R.W., Dan, Y. & Hensch, T.K. Removing brakes on adult brain plasticity: from molecular to behavioral interventions. J. Neurosci. 30, 14964–14971 (2010).

    Article  CAS  Google Scholar 

  34. Morishita, H., Miwa, J.M., Heintz, N. & Hensch, T.K. Lynx1, a cholinergic brake, limits plasticity in adult visual cortex. Science 330, 1238–1240 (2010).

    Article  CAS  Google Scholar 

  35. McGee, A.W., Yang, Y., Fischer, Q.S., Daw, N.W. & Strittmatter, S.M. Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor. Science 309, 2222–2226 (2005).

    Article  CAS  Google Scholar 

  36. Harauzov, A. et al. Reducing intracortical inhibition in the adult visual cortex promotes ocular dominance plasticity. J. Neurosci. 30, 361–371 (2010).

    Article  CAS  Google Scholar 

  37. Jiang, B., Huang, Z.J., Morales, B. & Kirkwood, A. Maturation of GABAergic transmission and the timing of plasticity in visual cortex. Brain Res. Brain Res. Rev. 50, 126–133 (2005).

    Article  CAS  Google Scholar 

  38. Schwaller, B. et al. Parvalbumin deficiency affects network properties resulting in increased susceptibility to epileptic seizures. Mol. Cell. Neurosci. 25, 650–663 (2004).

    Article  CAS  Google Scholar 

  39. Rudy, B. & McBain, C.J. Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing. Trends Neurosci. 24, 517–526 (2001).

    Article  CAS  Google Scholar 

  40. Carulli, D. et al. Animals lacking link protein have attenuated perineuronal nets and persistent plasticity. Brain 133, 2331–2347 (2010).

    Article  Google Scholar 

  41. Tropea, D. et al. Gene expression changes and molecular pathways mediating activity-dependent plasticity in visual cortex. Nat. Neurosci. 9, 660–668 (2006).

    Article  CAS  Google Scholar 

  42. Miyata, S., Nishimura, Y., Hayashi, N. & Oohira, A. Construction of perineuronal net–like structure by cortical neurons in culture. Neuroscience 136, 95–104 (2005).

    Article  CAS  Google Scholar 

  43. Lander, C., Zhang, H. & Hockfield, S. Neurons produce a neuronal cell surface–associated chondroitin sulfate proteoglycan. J. Neurosci. 18, 174–183 (1998).

    Article  CAS  Google Scholar 

  44. Chang, M.C. et al. Narp regulates homeostatic scaling of excitatory synapses on parvalbumin-expressing interneurons. Nat. Neurosci. 13, 1090–1097 (2010).

    Article  CAS  Google Scholar 

  45. Lewis, D.A., Hashimoto, T. & Volk, D.W. Cortical inhibitory neurons and schizophrenia. Nat. Rev. Neurosci. 6, 312–324 (2005).

    Article  CAS  Google Scholar 

  46. Pantazopoulos, H., Woo, T.U., Lim, M.P., Lange, N. & Berretta, S. Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch. Gen. Psychiatry 67, 155–166 (2010).

    Article  Google Scholar 

  47. Niwa, H., Yamamura, K. & Miyazaki, J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108, 193–199 (1991).

    Article  CAS  Google Scholar 

  48. Kitagawa, H., Kinoshita, A. & Sugahara, K. Microanalysis of glycosaminoglycan-derived disaccharides labeled with the fluorophore 2-aminoacridone by capillary electrophoresis and high-performance liquid chromatography. Anal. Biochem. 232, 114–121 (1995).

    Article  CAS  Google Scholar 

  49. Yoshimura, Y. et al. Involvement of T-type Ca2+ channels in the potentiation of synaptic and visual responses during the critical period in rat visual cortex. Eur. J. Neurosci. 28, 730–743 (2008).

    Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Hiroshi Kitagawa.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Table 1 (PDF 1586 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.3023

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing