title: Unmasking Proteolytic Activity for Adult Visual Cortex Plasticity by the Removal of Lynx1.
abstract: Experience-dependent cortical plasticity declines with age. At the molecular level, experience-dependent proteolytic activity of tissue plasminogen activator (tPA) becomes restricted in the adult brain if mice are raised in standard cages. Understanding the mechanism for the loss of permissive proteolytic activity is therefore a key link for improving function in adult brains. Using the mouse primary visual cortex (V1) as a model, we demonstrate that tPA activity in V1 can be unmasked following 4 d of monocular deprivation when the mice older than 2 months are raised in standard cages by the genetic removal of Lynx1, a negative regulator of adult plasticity. This was also associated with the reduction of stubby and thin spine density and enhancement of ocular dominance shift in adult V1 of Lynx1 knock-out (KO) mice. These structural and functional changes were tPA-dependent because genetic removal of tPA in Lynx1 KO mice can block the monocular deprivation-dependent reduction of dendritic spine density, whereas both genetic and adult specific inhibition of tPA activity can ablate the ocular dominance shift in Lynx1 KO mice. Our work demonstrates that the adult brain has an intrinsic potential for experience-dependent elevation of proteolytic activity to express juvenile-like structural and functional changes but is effectively limited by Lynx1 if mice are raised in standard cages. Insights into the Lynx1-tPA plasticity mechanism may provide novel therapeutic targets for adult brain disorders.
  
  
  CONCLUSIONS
  Experience-dependent proteolytic activity of tissue plasminogen activator (tPA) becomes restricted in the adult brain in correlation with the decline in cortical plasticity when mice are raised in standard cages. We demonstrated that removal of Lynx1, one of negative regulators of plasticity, unmasks experience-dependent tPA elevation in visual cortex of adult mice reared in standard cages. This proteolytic elevation facilitated dendritic spine reduction and ocular dominance plasticity in adult visual cortex. This is the first demonstration of adult brain to retain the intrinsic capacity to elevate tPA in an experience-dependent manner but is effectively limited by Lynx1. tPA-Lynx1 may potentially be a new candidate mechanism for interventions that were shown to activate plasticity in adult brain.
authors.affiliation: Departments of Psychiatry, Neuroscience, and Ophthalmology, Mindich Child Health and Development Institute, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Noreen
authors.initials: N
authors.lastname: Bukhari
authors.affiliation: Departments of Psychiatry, Neuroscience, and Ophthalmology, Mindich Child Health and Development Institute, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Poromendro N
authors.initials: PN
authors.lastname: Burman
authors.affiliation: Departments of Psychiatry, Neuroscience, and Ophthalmology, Mindich Child Health and Development Institute, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Ayan
authors.initials: A
authors.lastname: Hussein
authors.affiliation: Departments of Psychiatry, Neuroscience, and Ophthalmology, Mindich Child Health and Development Institute, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Demars
authors.affiliation: Departments of Psychiatry, Neuroscience, and Ophthalmology, Mindich Child Health and Development Institute, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Masato
authors.initials: M
authors.lastname: Sadahiro
authors.affiliation: Department of Physiology, University of California at San Francisco, San Francisco, California 94143, and.
authors.forename: Daniel M
authors.identifier: http://orcid.org/0000-0002-2112-8682
authors.initials: DM
authors.lastname: Brady
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794.
authors.forename: Stella E
authors.initials: SE
authors.lastname: Tsirka
authors.affiliation: Neuroscience, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
authors.affiliation: Departments of Psychiatry, Neuroscience, and Ophthalmology, Mindich Child Health and Development Institute, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, hirofumi.morishita@mssm.edu.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Morishita
mesh_terms: D000200:Action Potentials; D048868:Adaptor Proteins, Signal Transducing; D000375:Aging / Q000502:physiology; D000818:Animals; D001766:Blindness / Q000503:physiopathology; D049229:Dendritic Spines / Q000648:ultrastructure; D023882:Dominance, Ocular; D004777:Environment; D005260:Female; D017930:Genes, Reporter; D006799:Housing, Animal; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012683:Sensory Deprivation / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000502:physiology*; D014793:Visual Cortex / Q000503:physiopathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C120222:Lynx1 protein, mouse; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D010959:Tissue Plasminogen Activator
keywords: Lynx1; ocular dominance; plasticity; spine; tPA; visual cortex