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Cited by 82Neurogenesis and neuroplasticity mechanismsNeuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental Disorders

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

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Lee, H H C, Bernard, C, Ye, Z, Acampora, D, Simeone, A, Prochiantz, A, Di Nardo, A A, Hensch, T K·2017·Molecular Psychiatry
DOI 10.1038/mp.2017.1PMC PMC5400722
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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.

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  1. [1]Hensch TK Critical period plasticity in local cortical circuits Nature reviews Neuroscience 2005 6 11 877 888 16261181
  2. [3]Wang BS Sarnaik R Cang J Critical period plasticity matches binocular orientation preference in the visual cortex Neuron 2010 65 2 246 256 20152130 PMC2822731
  3. [4]Sanke RF Amblyopia American family physician 1988 37 2 275 278 3278568
  4. [5]Fagiolini M Hensch TK Inhibitory threshold for critical-period activation in primary visual cortex Nature 2000 404 6774 183 186 10724170
  5. [6]Gogolla N Leblanc JJ Quast KB Sudhof TC Fagiolini M Hensch TK Common circuit defect of excitatory-inhibitory balance in mouse models of autism Journal of neurodevelopmental disorders 2009 1 2 172 181 20664807 PMC2906812
  6. [7]Lewis DA Curley AA Glausier JR Volk DW Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia Trends in neurosciences 2012 35 1 57 67 22154068 PMC3253230
  7. [8]Kimoto S Bazmi HH Lewis DA Lower expression of glutamic acid decarboxylase 67 in the prefrontal cortex in schizophrenia: contribution of altered regulation by Zif268 The American journal of psychiatry 2014 171 9 969 978 24874453 PMC4376371
  8. [9]Uchida T Furukawa T Iwata S Yanagawa Y Fukuda A Selective loss of parvalbumin-positive GABAergic interneurons in the cerebral cortex of maternally stressed Gad1-heterozygous mouse offspring Translational psychiatry 2014 4 e371 24618690 PMC3966041
  9. [10]Failor S Nguyen V Darcy DP Cang J Wendland MF Stryker MP Neonatal cerebral hypoxia-ischemia impairs plasticity in rat visual cortex The Journal of neuroscience: the official journal of the Society for Neuroscience 2010 30 1 81 92 20053890 PMC2822440
  10. [11]Do KQ Cuenod M Hensch TK Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia Schizophrenia bulletin 2015 41 4 835 846 26032508 PMC4466197
  11. [12]LeBlanc JJ Fagiolini M Autism: a "critical period" disorder? Neural Plast 2011 2011 921680 21826280 PMC3150222
  12. [13]Le Magueresse C Monyer H GABAergic interneurons shape the functional maturation of the cortex Neuron 2013 77 3 388 405 23395369
  13. [17]Sabunciyan S Yolken R Ragan CM Potash JB Nimgaonkar VL Dickerson F Polymorphisms in the homeobox gene OTX2 may be a risk factor for bipolar disorder American journal of medical genetics Part B, Neuropsychiatric genetics: the official publication of the International Society of Psychiatric Genetics 2007 144B 8 1083 1086 17541950
  14. [21]Bernard C Kim HT Torero Ibad R Lee EJ Simonutti M Picaud S Graded Otx2 activities demonstrate dose-sensitive eye and retina phenotypes Human molecular genetics 2014 23 7 1742 1753 24234651
  15. [25]Acampora D Di Giovannantonio LG Di Salvio M Mancuso P Simeone A Selective inactivation of Otx2 mRNA isoforms reveals isoform-specific requirement for visceral endoderm anteriorization and head morphogenesis and highlights cell diversity in the visceral endoderm Mechanisms of development 2009 126 10 882 897 19615442
  16. [26]Acampora D Mazan S Lallemand Y Avantaggiato V Maury M Simeone A Forebrain and midbrain regions are deleted in Otx2-/- mutants due to a defective anterior neuroectoderm specification during gastrulation Development 1995 121 10 3279 3290 7588062
  17. [27]Nishida A Furukawa A Koike C Tano Y Aizawa S Matsuo I Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development Nature neuroscience 2003 6 12 1255 1263 14625556
  18. [28]Kang E Durand S LeBlanc JJ Hensch TK Chen C Fagiolini M Visual acuity development and plasticity in the absence of sensory experience The Journal of neuroscience: the official journal of the Society for Neuroscience 2013 33 45 17789 17796 24198369 PMC3818552
  19. [29]Takesian AE Hensch TK Balancing plasticity/stability across brain development Progress in brain research 2013 207 3 34 24309249
  20. [30]Garvert MM Moutoussis M Kurth-Nelson Z Behrens TE Dolan RJ Learning-induced plasticity in medial prefrontal cortex predicts preference malleability Neuron 2015 85 2 418 428 25611512 PMC4306543
  21. [32]Carulli D Pizzorusso T Kwok JC Putignano E Poli A Forostyak S Animals lacking link protein have attenuated perineuronal nets and persistent plasticity Brain: a journal of neurology 2010 133 Pt 8 2331 2347 20566484
  22. [34]Oohashi T Edamatsu M Bekku Y Carulli D The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity Exp Neurol 2015 274 Pt B 134 144 26387938
  23. [37]Stephany CE Chan LL Parivash SN Dorton HM Piechowicz M Qiu S Plasticity of binocularity and visual acuity are differentially limited by nogo receptor The Journal of neuroscience: the official journal of the Society for Neuroscience 2014 34 35 11631 11640 25164659 PMC4145169
  24. [38]Sato T Kudo T Ikehara Y Ogawa H Hirano T Kiyohara K Chondroitin sulfate N-acetylgalactosaminyltransferase 1 is necessary for normal endochondral ossification and aggrecan metabolism J Biol Chem 2011 286 7 5803 5812 21148564 PMC3037693
  25. [39]Rossier J Bernard A Cabungcal JH Perrenoud Q Savoye A Gallopin T Cortical fast-spiking parvalbumin interneurons enwrapped in the perineuronal net express the metallopeptidases Adamts8, Adamts15 and Neprilysin Molecular psychiatry 2015 20 2 154 161 25510509 PMC4356748
  26. [40]Valenzuela JC Heise C Franken G Singh J Schweitzer B Seidenbecher CI Hyaluronan-based extracellular matrix under conditions of homeostatic plasticity Philosophical transactions of the Royal Society of London Series B, Biological sciences 2014 369 1654 20130606 25225099 PMC4173291
  27. [41]Zeisel A Munoz-Manchado AB Codeluppi S Lonnerberg P La Manno G Jureus A Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq Science 2015 347 6226 1138 1142 25700174
  28. [42]Prochiantz A Di Nardo AA Homeoprotein signaling in the developing and adult nervous system Neuron 2015 85 5 911 925 25741720 PMC5031187
  29. [43]Kobayashi Y Ye Z Hensch TK Clock genes control cortical critical period timing Neuron 2015 86 1 264 275 25801703 PMC4392344
  30. [44]Gu Y Huang S Chang MC Worley P Kirkwood A Quinlan EM Obligatory role for the immediate early gene NARP in critical period plasticity Neuron 2013 79 2 335 346 23889936 PMC3804028
  31. [45]Vo T Carulli D Ehlert EM Kwok JC Dick G Mecollari V The chemorepulsive axon guidance protein semaphorin3A is a constituent of perineuronal nets in the adult rodent brain Molecular and cellular neurosciences 2013 56 186 200 23665579
  32. [46]Giamanco KA Matthews RT Deconstructing the perineuronal net: cellular contributions and molecular composition of the neuronal extracellular matrix Neuroscience 2012 218 367 384 22659016 PMC3400135
  33. [47]Tsien RY Very long-term memories may be stored in the pattern of holes in the perineuronal net Proceedings of the National Academy of Sciences of the United States of America 2013 110 30 12456 12461 23832785 PMC3725115
  34. [48]Werker JF Hensch TK Critical periods in speech perception: new directions Annual review of psychology 2015 66 173 196 25251488
  35. [49]Meredith RM Dawitz J Kramvis I Sensitive time-windows for susceptibility in neurodevelopmental disorders Trends in neurosciences 2012 35 6 335 344 22542246
  36. [50]Maeda N Proteoglycans and neuronal migration in the cerebral cortex during development and disease Frontiers in neuroscience 2015 9 98 25852466 PMC4369650
  37. [51]Gogolla N Takesian AE Feng G Fagiolini M Hensch TK Sensory integration in mouse insular cortex reflects GABA circuit maturation Neuron 2014 83 4 894 905 25088363 PMC4177076
  38. [53]Mauney SA Athanas KM Pantazopoulos H Shaskan N Passeri E Berretta S Developmental pattern of perineuronal nets in the human prefrontal cortex and their deficit in schizophrenia Biological psychiatry 2013 74 6 427 435 23790226 PMC3752333
  39. [54]Pantazopoulos H Woo TU Lim MP Lange N Berretta S Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia Archives of general psychiatry 2010 67 2 155 166 20124115 PMC4208310
  40. [55]Krishnan K Wang BS Lu J Wang L Maffei A Cang J Huang ZJ MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex Proc Natl Acad Sci U S A 2015 112 34 E4782 91 26261347 PMC4553776
  41. [56]Belichenko PV Hagberg B Dahlstrom A Morphological study of neocortical areas in Rett syndrome Acta neuropathologica 1997 93 1 50 61 9006657
  42. [57]Yizhar O Fenno LE Prigge M Schneider F Davidson TJ O'Shea DJ Neocortical excitation/inhibition balance in information processing and social dysfunction Nature 2011 477 7363 171 178 21796121 PMC4155501
  43. [58]Brown JA Ramikie TS Schmidt MJ Baldi R Garbett K Everheart MG Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes Molecular psychiatry 2015 PMC4516717 25623945
  44. [59]Akbarian S Kim JJ Potkin SG Hagman JO Tafazzoli A Bunney WE Jr Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics Archives of general psychiatry 1995 52 4 258 266 7702443
  45. [60]Hashimoto T Volk DW Eggan SM Mirnics K Pierri JN Sun Z Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia The Journal of neuroscience: the official journal of the Society for Neuroscience 2003 23 15 6315 6326 12867516 PMC6740534
  46. [62]Turner CA Thompson RC Bunney WE Schatzberg AF Barchas JD Myers RM Altered choroid plexus gene expression in major depressive disorder Frontiers in human neuroscience 2014 8 238 24795602 PMC4001046
  47. [63]Roybal K Theobold D Graham A DiNieri JA Russo SJ Krishnan V Mania-like behavior induced by disruption of CLOCK Proceedings of the National Academy of Sciences of the United States of America 2007 104 15 6406 6411 17379666 PMC1851061
  48. [64]Rekaik H Blaudin de The FX Fuchs J Massiani-Beaudoin O Prochiantz A Joshi RL Engrailed Homeoprotein Protects Mesencephalic Dopaminergic Neurons from Oxidative Stress Cell reports 2015 13 2 242 250 26411690 PMC5066840
  49. [65]Yinger OS Gooding L Music therapy and music medicine for children and adolescents Child and adolescent psychiatric clinics of North America 2014 23 3 535 553 24975624
  50. [66]Prusky GT Alam NM Beekman S Douglas RM Rapid quantification of adult and developing mouse spatial vision using a virtual optomotor system Investigative ophthalmology & visual science 2004 45 12 4611 4616 15557474
  51. [67]Abdeljalil J Hamid M Abdel-Mouttalib O Stephane R Raymond R Johan A The optomotor response: a robust first-line visual screening method for mice Vision research 2005 45 11 1439 1446 15743613

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Authors
Lee, H. H. C., Bernard, C., Ye, Z., Acampora, D., Simeone, A., Prochiantz, A., Di Nardo, A. A., & Hensch, T. K.
Affiliations
  • Boston Children's Hospital (US)
  • Centre National de la Recherche Scientifique (FR)
  • Harvard University (US)
  • Istituto Neurologico Mediterraneo (IT)
Corresponding author
Hensch, T K
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2017-02-14
Volume
22
Issue
5
Pages
680-688
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/mp.2017.1
PMC
PMC5400722
OpenAlex
W2588700717
Cited by
82
References
16
Citations by year
2026: 3 · 2025: 9 · 2024: 8 · 2023: 6 · 2022: 8 · 2021: 13 · 2020: 9 · 2019: 9 · 2018: 11 · 2017: 6
FWCI
4.05
Type
journal article
Language
en
Update notices
erratum (2017-04-04)
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • HAL (submittedVersion)
Funders
  • Agence Nationale de la Recherche (ANR-10-LABX-0054)
  • National Institute of Mental Health (P50MH094271, R01MH104488)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
Otx2, critical period plasticity, parvalbumin interneurons, visual cortex, primary auditory cortex, medial prefrontal cortex, perineuronal nets, tonotopic map, anxiety, interneuron maturation
MeSH terms
Protein Domains, Animals, Auditory Cortex, Cell Line, Extracellular Matrix, Glycosaminoglycans, Interneurons, Mice, Inbred Strains, Neuronal Plasticity, Parvalbumins, Visual Cortex, Point Mutation, Prefrontal Cortex, Mice, Otx Transcription Factors, Gene Knock-In Techniques

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