title: Genetic Otx2 mis-localization delays critical period plasticity across brain regions.
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.
authors.affiliation: FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: H H C
authors.initials: HHC
authors.lastname: Lee
authors.affiliation: Center for Interdisciplinary Research in Biology (CIRB), CNRS UMR 7241/INSERM U1050, Labex Memolife, Collège de France, Paris, France.
authors.forename: C
authors.identifier: 0000-0001-5305-7738
authors.initials: C
authors.lastname: Bernard
authors.affiliation: Center for Brain Science, Department of Molecular Cellular Biology, Harvard University, Cambridge, MA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso', Naples, Italy.|IRCCS Neuromed, Pozzilli, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Acampora
authors.affiliation: Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso', Naples, Italy.|IRCCS Neuromed, Pozzilli, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Simeone
authors.affiliation: Center for Interdisciplinary Research in Biology (CIRB), CNRS UMR 7241/INSERM U1050, Labex Memolife, Collège de France, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Prochiantz
authors.affiliation: Center for Interdisciplinary Research in Biology (CIRB), CNRS UMR 7241/INSERM U1050, Labex Memolife, Collège de France, Paris, France.
authors.forename: A A
authors.initials: AA
authors.lastname: Di Nardo
authors.affiliation: FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.|Center for Brain Science, Department of Molecular Cellular Biology, Harvard University, Cambridge, MA, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: Hensch
mesh_terms: D000818:Animals; D001303:Auditory Cortex / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D005109:Extracellular Matrix / Q000378:metabolism; D055879:Gene Knock-In Techniques; D006025:Glycosaminoglycans / Q000378:metabolism; D007395:Interneurons / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D009473:Neuronal Plasticity / Q000235:genetics* / Q000502:physiology; D051857:Otx Transcription Factors / Q000235:genetics* / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D017354:Point Mutation; D017397:Prefrontal Cortex / Q000378:metabolism / Q000502:physiology*; D000072417:Protein Domains; D014793:Visual Cortex / Q000378:metabolism
chemical_list: D006025:Glycosaminoglycans; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D010320:Parvalbumins