Browsing by Author "Bukhari, Noreen"

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    Axonal regrowth after spinal cord injury via chondroitinase and the tissue plasminogen activator (tPA)/plasmin system.
    (The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011-10) Bukhari, Noreen; Torres, Luisa; Robinson, John K; Tsirka, Stella E
    Spinal cord injury (SCI) causes permanent debilitation due to the inability of axons to grow through established scars. Both the sugar chains and core proteins of chondroitin sulfate proteoglycans (CSPGs) are inhibitory for neurite regrowth. Chondroitinase ABC (ChABC) degrades the sugar chains and allows for synaptic plasticity, suggesting that after the sugar chain cleavage additional steps occur promoting a permissive microenvironment in the glial scar region. We report that the clearance of the core protein by the tissue plasminogen activator (tPA)/plasmin proteolytic system partially contributes to ChABC-promoted plasticity. tPA and plasmin are upregulated after SCI and degrade the deglycosylated CSPG proteins. Mice lacking tPA (tPA(-/-)) exhibit attenuated neurite outgrowth and blunted sensory and motor recovery despite ChABC treatment. Coadministration of ChABC and plasmin enhanced the tPA(-/-) phenotype and supported recovery in WT SCI mice. Collectively, these findings show that the tPA/plasmin cascade may act downstream of ChABC to allow for synergistic sensory and motor improvement compared with each treatment alone and suggest a potential new approach to enhance functional recovery after SCI.
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    Unmasking Proteolytic Activity for Adult Visual Cortex Plasticity by the Removal of Lynx1.
    (The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015-09) Bukhari, Noreen; Burman, Poromendro N; Hussein, Ayan; Demars, Michael P; Sadahiro, Masato; Brady, Daniel M; Tsirka, Stella E; Russo, Scott J; Morishita, Hirofumi

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    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.

    Significance statement

    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.