Original Article

Molecular Psychiatry (2017) 22, 680–688; doi:10.1038/mp.2017.1 published online 14 February 2017

There is an Erratum (21 April 2017) associated with this article.

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

H H C Lee1,6, C Bernard2,6, Z Ye3,6, D Acampora4,5, A Simeone4,5, A Prochiantz2, A A Di Nardo2 and T K Hensch1,3

  1. 1FM Kirby Neurobiology Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
  2. 2Center for Interdisciplinary Research in Biology (CIRB), CNRS UMR 7241/INSERM U1050, Labex Memolife, Collège de France, Paris, France
  3. 3Center for Brain Science, Department of Molecular Cellular Biology, Harvard University, Cambridge, MA, USA
  4. 4Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso', Naples, Italy
  5. 5IRCCS Neuromed, Pozzilli, Italy

Correspondence: AA Di Nardo, Center for Interdisciplinary Research in Biology, CNRS UMR 7241/INSERM U1050, Labex Memolife, Collège de France, Paris, FranceE-mail: ariel.dinardo@college-de-france.fr; Professor TK Hensch, Center for Brain Science, Department of Molecular Cellular Biology, Harvard University, 52 Oxford Street (NW 347.10), Cambridge, MA 02138, USA. E-mail: hensch@mcb.harvard.edu

6These authors contributed equally to this work.

Received 27 April 2016; Revised 21 November 2016; Accepted 21 December 2016
Advance online publication 14 February 2017

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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.