Original Article | Published:

Genetic Otx2 mis-localization delays critical period plasticity across brain regions

Molecular Psychiatry volume 22, pages 680688 (2017) | Download Citation

  • An Erratum to this article was published on 04 April 2017

Abstract

Accumulation of non-cell autonomous Otx2 homeoprotein in postnatal mouse visual cortex (V1) has been implicated in both the onset and closure of critical period (CP) plasticity. Here, we show that a genetic point mutation in the glycosaminoglycan recognition motif of Otx2 broadly delays the maturation of pivotal parvalbumin-positive (PV+) interneurons not only in V1 but also in the primary auditory (A1) and medial prefrontal cortex (mPFC). Consequently, not only visual, but also auditory plasticity is delayed, including the experience-dependent expansion of tonotopic maps in A1 and the acquisition of acoustic preferences in mPFC, which mitigates anxious behavior. In addition, Otx2 mis-localization leads to dynamic turnover of selected perineuronal net (PNN) components well beyond the normal CP in V1 and mPFC. These findings reveal widespread actions of Otx2 signaling in the postnatal cortex controlling the maturational trajectory across modalities. Disrupted PV+ network function and deficits in PNN integrity are implicated in a variety of psychiatric illnesses, suggesting a potential global role for Otx2 function in establishing mental health.

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Acknowledgements

We thank M Nakamura for mouse maintenance; and support from NIH (1P50MH094271 and 1R01MH104488 to TKH), the Italian Association for Cancer Research (AIRC) (grant IG2013 N° 14152 to AS) and Fondation Bettencourt Schueller, ERC Advanced Grant HOMEOSIGN n° 339379 and ANR (ANR-11-BLAN-069467) (to AP). HHCL and ZY were further supported, respectively, by a post-doctoral fellowship from the Croucher Foundation (Hong Kong) and a Julius B Richmond predoctoral fellowship.

Author information

Author notes

    • H H C Lee
    • , C Bernard
    •  & Z Ye

    These authors contributed equally to this work.

Affiliations

  1. FM Kirby Neurobiology Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    • H H C Lee
    •  & T K Hensch
  2. Center for Interdisciplinary Research in Biology (CIRB), CNRS UMR 7241/INSERM U1050, Labex Memolife, Collège de France, Paris, France

    • C Bernard
    • , A Prochiantz
    •  & A A Di Nardo
  3. Center for Brain Science, Department of Molecular Cellular Biology, Harvard University, Cambridge, MA, USA

    • Z Ye
    •  & T K Hensch
  4. Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso', Naples, Italy

    • D Acampora
    •  & A Simeone
  5. IRCCS Neuromed, Pozzilli, Italy

    • D Acampora
    •  & A Simeone

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The authors declare no conflict of interest.

Corresponding authors

Correspondence to A A Di Nardo or T K Hensch.

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DOI

https://doi.org/10.1038/mp.2017.1

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)