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Ube3a is required for experience-dependent maturation of the neocortex

Nature Neuroscience volume 12, pages 777–783 (2009)Cite this article

Abstract

Experience-dependent maturation of neocortical circuits is required for normal sensory and cognitive abilities, which are distorted in neurodevelopmental disorders. We tested whether experience-dependent neocortical modifications require Ube3a, an E3 ubiquitin ligase whose dysregulation has been implicated in autism and Angelman syndrome. Using visual cortex as a model, we found that experience-dependent maturation of excitatory cortical circuits was severely impaired in Angelman syndrome model mice deficient in Ube3a. This developmental defect was associated with profound impairments in neocortical plasticity. Normal plasticity was preserved under conditions of sensory deprivation, but was rapidly lost by sensory experiences. The loss of neocortical plasticity is reversible, as late-onset visual deprivation restored normal synaptic plasticity. Furthermore, Ube3a-deficient mice lacked ocular dominance plasticity in vivo when challenged with monocular deprivation. We conclude that Ube3a is necessary for maintaining plasticity during experience-dependent neocortical development and suggest that the loss of neocortical plasticity contributes to deficits associated with Angelman syndrome.

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Figure 1: Reduced functional maturation of neocortical synapses in Angelman syndrome mice.
Figure 2: Sensory experience augments excitatory synaptic connections in the neocortex of WT mice, but not Angelman syndrome mice.
Figure 3: Synaptic plasticity is impaired bidirectionally in the neocortex of Angelman syndrome mice.
Figure 4: Sensory experience eliminates neocortical plasticity in Angelman syndrome mice.
Figure 5: LOVD restores synaptic plasticity in Angelman syndrome mice.
Figure 6: Critical period ocular dominance plasticity is absent in Angelman syndrome mice.

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References

  1. Clayton-Smith, J. & Laan, L. Angelman syndrome: a review of the clinical and genetic aspects. J. Med. Genet. 40, 87–95 (2003).

    Article  CAS  Google Scholar 

  2. Jiang, Y.H. et al. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 21, 799–811 (1998).

    Article  CAS  Google Scholar 

  3. Rougeulle, C., Glatt, H. & Lalande, M. The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat. Genet. 17, 14–15 (1997).

    Article  CAS  Google Scholar 

  4. Schroer, R.J. et al. Autism and maternally derived aberrations of chromosome 15q. Am. J. Med. Genet. 76, 327–336 (1998).

    Article  CAS  Google Scholar 

  5. Albrecht, U. et al. Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat. Genet. 17, 75–78 (1997).

    Article  CAS  Google Scholar 

  6. Dindot, S.V., Antalffy, B.A., Bhattacharjee, M.B. & Beaudet, A.L. The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum. Mol. Genet. 17, 111–118 (2007).

    Article  Google Scholar 

  7. Zoghbi, H.Y. Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302, 826–830 (2003).

    Article  CAS  Google Scholar 

  8. Weeber, E.J. et al. Derangements of hippocampal calcium/calmodulin-dependent protein kinase II in a mouse model for Angelman mental retardation syndrome. J. Neurosci. 23, 2634–2644 (2003).

    Article  CAS  Google Scholar 

  9. van Woerden, G.M. et al. Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of αCaMKII inhibitory phosphorylation. Nat. Neurosci. 10, 280–282 (2007).

    Article  CAS  Google Scholar 

  10. Yi, J.J. & Ehlers, M.D. Ubiquitin and protein turnover in synapse function. Neuron 47, 629–632 (2005).

    Article  CAS  Google Scholar 

  11. Yi, J.J. & Ehlers, M.D. Emerging roles for ubiquitin and protein degradation in neuronal function. Pharmacol. Rev. 59, 14–39 (2007).

    Article  CAS  Google Scholar 

  12. Walz, N.C. & Baranek, G.T. Sensory processing patterns in persons with Angelman syndrome. Am. J. Occup. Ther. 60, 472–479 (2006).

    Article  Google Scholar 

  13. Williams, C.A. et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am. J. Med. Genet. A. 140, 413–418 (2006).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Fagiolini, M. et al. Separable features of visual cortical plasticity revealed by N-methyl-d-aspartate receptor 2A signaling. Proc. Natl. Acad. Sci. USA 100, 2854–2859 (2003).

    Article  CAS  Google Scholar 

  16. Gianfranceschi, L. et al. Visual cortex is rescued from the effects of dark rearing by overexpression of BDNF. Proc. Natl. Acad. Sci. USA 100, 12486–12491 (2003).

    Article  CAS  Google Scholar 

  17. Li, Y., Fitzpatrick, D. & White, L.E. The development of direction selectivity in ferret visual cortex requires early visual experience. Nat. Neurosci. 9, 676–681 (2006).

    Article  CAS  Google Scholar 

  18. Wallace, W. & Bear, M.F. A morphological correlate of synaptic scaling in visual cortex. J. Neurosci. 24, 6928–6938 (2004).

    Article  CAS  Google Scholar 

  19. Philpot, B.D., Sekhar, A.K., Shouval, H.Z. & Bear, M.F. Visual experience and deprivation bidirectionally modify the composition and function of NMDA receptors in visual cortex. Neuron 29, 157–169 (2001).

    Article  CAS  Google Scholar 

  20. Kirkwood, A., Rioult, M.G. & Bear, M.F. Experience-dependent modification of synaptic plasticity in visual cortex. Nature 381, 526–528 (1996).

    Article  CAS  Google Scholar 

  21. Jordan, C. & Francke, U. Ube3a expression is not altered in Mecp2 mutant mice. Hum. Mol. Genet. 15, 2210–2215 (2006).

    Article  CAS  Google Scholar 

  22. Vu, T.H. & Hoffman, A.R. Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. Nat. Genet. 17, 12–13 (1997).

    Article  CAS  Google Scholar 

  23. Mullen, R.J., Buck, C.R. & Smith, A.M. NeuN, a neuronal specific nuclear protein in vertebrates. Development 116, 201–211 (1992).

    CAS  PubMed  Google Scholar 

  24. Desai, N.S., Cudmore, R.H., Nelson, S.B. & Turrigiano, G.G. Critical periods for experience-dependent synaptic scaling in visual cortex. Nat. Neurosci. 5, 783–789 (2002).

    Article  CAS  Google Scholar 

  25. Goel, A. & Lee, H.K. Persistence of experience-induced homeostatic synaptic plasticity through adulthood in superficial layers of mouse visual cortex. J. Neurosci. 27, 6692–6700 (2007).

    Article  CAS  Google Scholar 

  26. Nimchinsky, E.A., Sabatini, B.L. & Svoboda, K. Structure and function of dendritic spines. Annu. Rev. Physiol. 64, 313–353 (2002).

    Article  CAS  Google Scholar 

  27. Kirkwood, A., Silva, A. & Bear, M.F. Age-dependent decrease of synaptic plasticity in the neocortex of αCaMKII mutant mice. Proc. Natl. Acad. Sci. USA 94, 3380–3383 (1997).

    Article  CAS  Google Scholar 

  28. Philpot, B.D., Cho, K.K. & Bear, M.F. Obligatory role of NR2A for metaplasticity in visual cortex. Neuron 53, 495–502 (2007).

    Article  CAS  Google Scholar 

  29. Jiang, B., Trevino, M. & Kirkwood, A. Sequential development of long-term potentiation and depression in different layers of the mouse visual cortex. J. Neurosci. 27, 9648–9652 (2007).

    Article  CAS  Google Scholar 

  30. He, H.Y., Hodos, W. & Quinlan, E.M. Visual deprivation reactivates rapid ocular dominance plasticity in adult visual cortex. J. Neurosci. 26, 2951–2955 (2006).

    Article  CAS  Google Scholar 

  31. 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 

  32. 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 

  33. Crozier, R.A., Wang, Y., Liu, C.H. & Bear, M.F. Deprivation-induced synaptic depression by distinct mechanisms in different layers of mouse visual cortex. Proc. Natl. Acad. Sci. USA 104, 1383–1388 (2007).

    Article  CAS  Google Scholar 

  34. Xia, Z. & Storm, D.R. The role of calmodulin as a signal integrator for synaptic plasticity. Nat. Rev. Neurosci. 6, 267–276 (2005).

    Article  CAS  Google Scholar 

  35. Silva, A.J., Stevens, C., Tonegawa, S. & Wang, Y. Deficient hippocampal long-term potentiation in α-calcium-calmodulin kinase II mutant mice. Science 257, 206–211 (1992).

    Article  CAS  Google Scholar 

  36. Frankland, P.W., O'Brien, C., Ohno, M., Kirkwood, A. & Silva, A.J. αCaMKII-dependent plasticity in the cortex is required for permanent memory. Nature 411, 309–313 (2001).

    Article  CAS  Google Scholar 

  37. Yasuda, H., Barth, A.L., Stellwagen, D. & Malenka, R.C. A developmental switch in the signaling cascades for LTP induction. Nat. Neurosci. 6, 15–16 (2003).

    Article  CAS  Google Scholar 

  38. Torii, N., Kamishita, T., Otsu, Y. & Tsumoto, T. An inhibitor for calcineurin, FK506, blocks induction of long-term depression in rat visual cortex. Neurosci. Lett. 185, 1–4 (1995).

    Article  CAS  Google Scholar 

  39. Mulkey, R.M., Endo, S., Shenolikar, S. & Malenka, R.C. Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature 369, 486–488 (1994).

    Article  CAS  Google Scholar 

  40. Fonseca, R., Vabulas, R.M., Hartl, F.U., Bonhoeffer, T. & Nagerl, U.V. A balance of protein synthesis and proteasome-dependent degradation determines the maintenance of LTP. Neuron 52, 239–245 (2006).

    Article  CAS  Google Scholar 

  41. Colledge, M. et al. Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 40, 595–607 (2003).

    Article  CAS  Google Scholar 

  42. Majdan, M. & Shatz, C.J. Effects of visual experience on activity-dependent gene regulation in cortex. Nat. Neurosci. 9, 650–659 (2006).

    Article  CAS  Google Scholar 

  43. 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 

  44. Heynen, A.J. et al. Molecular mechanism for loss of visual cortical responsiveness following brief monocular deprivation. Nat. Neurosci. 6, 854–862 (2003).

    Article  CAS  Google Scholar 

  45. Van Splunder, J., Stilma, J.S. & Evenhuis, H.M. Visual performance in specific syndromes associated with intellectual disability. Eur. J. Ophthalmol. 13, 566–574 (2003).

    Article  CAS  Google Scholar 

  46. Thompson, D.A., Kriss, A., Cottrell, S. & Taylor, D. Visual evoked potential evidence of albino-like chiasmal misrouting in a patient with Angelman syndrome with no ocular features of albinism. Dev. Med. Child Neurol. 41, 633–638 (1999).

    Article  CAS  Google Scholar 

  47. Jay, V., Becker, L.E., Chan, F.W. & Perry, T.L., Sr. Puppet-like syndrome of Angelman: a pathologic and neurochemical study. Neurology 41, 416–422 (1991).

    Article  CAS  Google Scholar 

  48. Gatenby, J. & Beams, H. Microscopist's Vade-Mecum 11th edn. (J. & A. Churchill, London, 1950).

    Google Scholar 

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Acknowledgements

We thank I. Davison, S. Dudek, P. Farel, P. Manis, R. Mooney, R. Sealock, M. Zylka and members of the Philpot and Ehlers laboratories for critically reading the manuscript and for helpful discussions. We also thank R. Larsen and P. Cao of the University of North Carolina (UNC) Summer Undergraduate Research Experience Program, R. Peterson at the UNC Confocal/Multiphoton Microscopy Core Facility, and Kirk McNaughton at the UNC Histology Facility for technical help. Special thanks to W. Boyes, J. deMarchena, L. Khibnik, R. Muhammad, and M. Bear for their assistance with the VEP technique. This work was supported by a UNC dissertation completion fellowship (K.Y.), a Ruth K. Broad Biomedical Research Foundation Graduate Student Research Award (K.H.C.), a Helen Lyng White Fellowship (A.C.R.), a National Institute of Child Health and Human Development training grant (T32-HD40127, A.C.R.), US National Institutes of Health grants NS039402 and AG024492 (M.D.E.), a National Institute of Neurological Disorders and Stroke grant (NS035527, R.J.W.), a National Eye Institute grant (R01EY018323, B.D.P.), and the Angelman Syndrome Foundation and Simons Foundation (B.D.P. and M.D.E.). M.D.E. is an Investigator of the Howard Hughes Medical Institute.

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  1. Koji Yashiro

    Present address: Present address: Urogenix, Inc., Durham, North Carolina, USA.,

Authors and Affiliations

  1. Department of Cell and Molecular Physiology University of North Carolina, Chapel Hill, North Carolina, USA

    Koji Yashiro, Thorfinn T Riday, Adam C Roberts, Danilo R Bernardo, Rohit Prakash & Benjamin D Philpot

  2. Curriculum in Neurobiology, University of North Carolina, Chapel Hill, North Carolina, USA

    Thorfinn T Riday & Benjamin D Philpot

  3. Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA

    Kathryn H Condon & Michael D Ehlers

  4. University of North Carolina Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina, USA

    Adam C Roberts, Richard J Weinberg & Benjamin D Philpot

  5. Neurodevelopmental Disorders Research Center, University of North Carolina, Chapel Hill, North Carolina, USA

    Adam C Roberts & Benjamin D Philpot

  6. Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, North Carolina, USA

    Richard J Weinberg

  7. Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina, USA

    Michael D Ehlers

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Contributions

K.Y., B.D.P. and M.D.E. designed the study and wrote the manuscript. K.Y. conducted immunohistochemistry, Golgi impregnation, whole-cell patch-clamp and field potential experiments. T.T.R. contributed to the field potential studies and conducted VEP experiments. K.H.C. contributed to the Golgi impregnation study and conducted immunoblot experiments. A.C.R. contributed to the whole-cell patch-clamp and field potential studies. D.R.B. contributed to the field potential studies. R.P. contributed to the VEP experiments. R.J.W. directed the Golgi impregnation experiments and helped to prepare the manuscript. M.D.E. and B.D.P. supervised the study.

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Correspondence to Michael D Ehlers or Benjamin D Philpot.

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Yashiro, K., Riday, T., Condon, K. et al. Ube3a is required for experience-dependent maturation of the neocortex. Nat Neurosci 12, 777–783 (2009). https://doi.org/10.1038/nn.2327

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