Otx2 Binding to Perineuronal Nets Persistently Regulates Plasticity in the Mature Visual Cortex

Specific transfer of (orthodenticle homeobox 2) Otx2 homeoprotein into GABAergic interneurons expressing parvalbumin (PV) is necessary and sufficient to open, then close, a critical period (CP) of plasticity in the developing mouse visual cortex. The accumulation of endogenous Otx2 in PV cells suggests the presence of specific Otx2 binding sites. Here, we find that perineuronal nets (PNNs) on the surfaces of PV cells permit the specific, constitutive capture of Otx2. We identify a 15 aa domain containing an arginine-lysine doublet (RK peptide) within Otx2, bearing prototypic traits of a glycosaminoglycan (GAG) binding sequence that mediates Otx2 binding to PNNs, and specifically to chondroitin sulfate D and E, with high affinity. Accordingly, PNN hydrolysis by chondroitinase ABC reduces the amount of endogenous Otx2 in PV cells. Direct infusion of RK peptide similarly disrupts endogenous Otx2 localization to PV cells, reduces PV and PNN expression, and reopens plasticity in adult mice. The closure of one eye during this transient window reduces cortical acuity and is specific to the RK motif, as an Alanine-Alanine variant or a scrambled peptide fails to reactivate plasticity. Conversely, this transient reopening of plasticity in the adult restores binocular vision in amblyopic mice. Thus, one function of PNNs is to facilitate the persistent internalization of Otx2 by PV cells to maintain CP closure. The pharmacological use of the Otx2 GAG binding domain offers a novel, potent therapeutic tool with which to restore cortical plasticity in the mature brain.

[1]  Yumiko Yoshimura,et al.  Persistent cortical plasticity by upregulation of chondroitin 6-sulfation , 2012, Nature Neuroscience.

[2]  A. Prochiantz,et al.  Engrailed homeoprotein recruits the adenosine A1 receptor to potentiate ephrin A5 function in retinal growth cones , 2012, Development.

[3]  A. Prochiantz,et al.  Paracrine Pax6 activity regulates oligodendrocyte precursor cell migration in the chick embryonic neural tube , 2011, Development.

[4]  Takao K. Hensch,et al.  Lynx1, a Cholinergic Brake, Limits Plasticity in Adult Visual Cortex , 2010, Science.

[5]  Daphne Bavelier,et al.  Removing Brakes on Adult Brain Plasticity: From Molecular to Behavioral Interventions , 2010, The Journal of Neuroscience.

[6]  J. Fawcett,et al.  Animals lacking link protein have attenuated perineuronal nets and persistent plasticity. , 2010, Brain : a journal of neurology.

[7]  S. Glazewski,et al.  Parvalbumin‐containing neurons, perineuronal nets and experience‐dependent plasticity in murine barrel cortex , 2009, The European journal of neuroscience.

[8]  C. Holt,et al.  Extracellular Engrailed Participates in the Topographic Guidance of Retinal Axons In Vivo , 2009, Neuron.

[9]  Siu Kang,et al.  Bidirectional plasticity in fast-spiking GABA circuits by visual experience , 2009, Nature.

[10]  T. Nick,et al.  Modulation of Perineuronal Nets and Parvalbumin with Developmental Song Learning , 2009, The Journal of Neuroscience.

[11]  Andreas Lüthi,et al.  Perineuronal Nets Protect Fear Memories from Erasure , 2009, Science.

[12]  T. Südhof,et al.  Common circuit defect of excitatory-inhibitory balance in mouse models of autism , 2009, Journal of Neurodevelopmental Disorders.

[13]  Konrad Lehmann,et al.  Age-Dependent Ocular Dominance Plasticity in Adult Mice , 2008, PloS one.

[14]  A. Prochiantz,et al.  Experience-Dependent Transfer of Otx2 Homeoprotein into the Visual Cortex Activates Postnatal Plasticity , 2008, Cell.

[15]  P. Thérond,et al.  Cellular trafficking of the glypican Dally-like is required for full-strength Hedgehog signaling and wingless transcytosis. , 2008, Developmental cell.

[16]  J. Seelig,et al.  Binding and clustering of glycosaminoglycans: a common property of mono- and multivalent cell-penetrating compounds. , 2008, Biophysical journal.

[17]  A. Ziegler,et al.  Thermodynamic studies and binding mechanisms of cell-penetrating peptides with lipids and glycosaminoglycans. , 2008, Advanced drug delivery reviews.

[18]  Takao K Hensch,et al.  Critical period revisited: impact on vision , 2008, Current Opinion in Neurobiology.

[19]  L. Maffei,et al.  Plasticity in the adult brain: lessons from the visual system , 2008, Experimental Brain Research.

[20]  A. Prochiantz,et al.  The topological role of homeoproteins in the developing central nervous system , 2007, Trends in Neurosciences.

[21]  S. Cruikshank,et al.  Synaptic basis for intense thalamocortical activation of feedforward inhibitory cells in neocortex , 2007, Nature Neuroscience.

[22]  Oliver Hobert,et al.  The molecular diversity of glycosaminoglycans shapes animal development. , 2006, Annual review of cell and developmental biology.

[23]  G. Giménez-Gallego,et al.  Heparan Sulfate-related Oligosaccharides in Ternary Complex Formation with Fibroblast Growth Factors 1 and 2 and Their Receptors* , 2006, Journal of Biological Chemistry.

[24]  Nicoletta Berardi,et al.  Structural and functional recovery from early monocular deprivation in adult rats. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[25]  C. Holt,et al.  The transcription factor Engrailed-2 guides retinal axons , 2005, Nature.

[26]  T. Hensch.  Critical period plasticity in local cortical circuits , 2005, Nature Reviews Neuroscience.

[27]  A. Erisir,et al.  Quantitative morphology and postsynaptic targets of thalamocortical axons in critical period and adult ferret visual cortex , 2005, The Journal of comparative neurology.

[28]  D. Lewis,et al.  Cortical inhibitory neurons and schizophrenia , 2005, Nature Reviews Neuroscience.

[29]  Nicoletta Berardi,et al.  Extracellular Matrix and Visual Cortical Plasticity Freeing the Synapse , 2004, Neuron.

[30]  Nobuko Mataga,et al.  Experience-Dependent Pruning of Dendritic Spines in Visual Cortex by Tissue Plasminogen Activator , 2004, Neuron.

[31]  T. Hensch.  Critical period regulation. , 2004, Annual review of neuroscience.

[32]  A. Prochiantz,et al.  Transduction peptides: from technology to physiology , 2004, Nature Cell Biology.

[33]  L. Maffei,et al.  Visual cortex is rescued from the effects of dark rearing by overexpression of BDNF , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Takao K. Hensch,et al.  Rapid Critical Period Induction by Tonic Inhibition in Visual Cortex , 2003, The Journal of Neuroscience.

[35]  Hisashi Mori,et al.  Separable features of visual cortical plasticity revealed by N-methyl-d-aspartate receptor 2A signaling , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  L. Maffei,et al.  Reactivation of Ocular Dominance Plasticity in the Adult Visual Cortex , 2002, Science.

[37]  Daniel E. Feldman,et al.  Inhibition and plasticity , 2000, Nature Neuroscience.

[38]  A. Reichenbach,et al.  Cortical neurons immunoreactive for the potassium channel Kv3.1b subunit are predominantly surrounded by perineuronal nets presumed as a buffering system for cations , 1999, Brain Research.

[39]  M. Stryker,et al.  Comparison of Plasticity In Vivo and In Vitro in the Developing Visual Cortex of Normal and Protein Kinase A RIβ-Deficient Mice , 1998, The Journal of Neuroscience.

[40]  Alcino J. Silva,et al.  Deficient Plasticity in the Primary Visual Cortex of α-Calcium/Calmodulin-Dependent Protein Kinase II Mutant Mice , 1996, Neuron.

[41]  M P Stryker,et al.  Experience-Dependent Plasticity of Binocular Responses in the Primary Visual Cortex of the Mouse , 1996, The Journal of Neuroscience.

[42]  J. Flanagan,et al.  Identification and cloning of ELF-1, a developmentally expressed ligand for the Mek4 and Sek receptor tyrosine kinases , 1994, Cell.

[43]  I. Blumcke,et al.  Perineuronal nets — a specialized form of extracellular matrix in the adult nervous system , 1994, Brain Research Reviews.

[44]  A. Prochiantz,et al.  alpha-2,8-Polysialic acid is the neuronal surface receptor of antennapedia homeobox peptide. , 1991, The New biologist.

[45]  A. Prochiantz,et al.  Antennapedia homeobox peptide regulates neural morphogenesis. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[46]  G. Mower,et al.  The effect of dark rearing on the time course of the critical period in cat visual cortex. , 1991, Brain research. Developmental brain research.

[47]  A. Cardin,et al.  Molecular Modeling of Protein‐Glycosaminoglycan Interactions , 1989, Arteriosclerosis.

[48]  D. Hubel,et al.  EFFECTS OF VISUAL DEPRIVATION ON MORPHOLOGY AND PHYSIOLOGY OF CELLS IN THE CATS LATERAL GENICULATE BODY. , 1963, Journal of neurophysiology.