The Tissue Plasminogen Activator (Tpa/Plasmin) Extracellular Proteolytic System Regulates Seizure-Induced Hippocampal Mossy Fiber Outgrowth through a Proteoglycan Substrate

Wu, Yan; Siao, Chia-Jen; Lu, Weiquan; Sung, Tsung-Chang; Frohman, Michael A.; Milev, Peter; Bugge, Thomas H.; Degen, Jay L.; Levine, Joel M.; Margolis, Richard U.; Tsirka, Stella E.

doi:10.1083/jcb.148.6.1295

Cited by 185 publications

(155 citation statements)

References 46 publications

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“…Studies using tPA À/À mice have also demonstrated that tPA contributes to pathological synaptic plasticity associated with epilepsy, including chemoconvulsant-induced pyramidal cell death 33 and mossy fibre sprouting. 34 In this study, we show that tPA enzyme activity is upregulated in limbic and cortical areas of the contralateral hemisphere at 4 h following electrically evoked seizures (Figure 3). Notably, one study documents a decrease in tPA activity at 24 h post-seizure.…”

Section: Discussionsupporting

confidence: 52%

Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation

Sashindranath

Samson

Downes

et al. 2011

Laboratory Investigation

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Tissue-type plasminogen activator (tPA) is a major protease of the central nervous system. Most studies to date have used in situ-or gel-based zymographic assays to monitor in vivo changes in neural tPA activity. In this study, we demonstrate that the amidolytic assay can be adapted to accurately detect changes in net tPA activity in mouse brain tissues. Using the amidolytic assay, we examined differences in net tPA activity in the cerebral cortex, sub-cortical structures and cerebellum in wildtype (WT) and tPA À/À mice, and in transgenic mice selectively overexpressing tPA in neurons. In addition, we assessed changes in endogenous net tPA activity in WT mice following morphine administration, epileptic seizures, traumatic brain injury and ischaemic stroke-neurological settings in which tPA has a known functional role. Under these conditions, acute and compartment-specific regulation of tPA activity was observed. tPA also participates in various forms of chronic neurodegeneration. Accordingly, we assessed tPA activity levels in mouse models of Alzheimer's disease (AD) and spinocerebellar ataxia type-1 (SCA1). Decreased tPA activity was detected in the cortex and subcortex of AD mice, whereas increased tPA activity was found in the cerebellum of SCA1 mice. These findings extend the existing hypotheses that low tPA activity promotes AD, whereas increased tPA activity contributes to cerebellar degeneration. Collectively, our results exemplify the utility of the amidolytic assay and emphasise tPA as a complex mediator of brain function and dysfunction. On the basis of this evidence, we propose that alterations in tPA activity levels could be used as a biomarker for perturbations in brain homeostasis.

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Section: Discussionsupporting

confidence: 52%

Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation

Sashindranath

Samson

Downes

et al. 2011

Laboratory Investigation

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“…CSPGs, distributed through the extracellular matrix, primarily contribute to the latter mechanism. However, because of their chemical heterogeneity and differential effect on distinct axon populations (Wu et al, 2000;Heck et al, 2004), they may serve as a fine-tuning system to regulate neuritic plasticity in a cell type-specific manner.…”

Section: Discussionmentioning

confidence: 99%

Degradation of Chondroitin Sulfate Proteoglycans Induces Sprouting of Intact Purkinje Axons in the Cerebellum of the Adult Rat

Corvetti¹,

Rossi²

2005

J. Neurosci.

123

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Chondroitin sulfate proteoglycans are major constituents of the extracellular matrix and form perineuronal nets. Information regarding the growth-inhibitory activity of these molecules after injury is rapidly expanding. However, less is known about their physiological role in the adult undamaged CNS. Here, we investigated the function of chondroitin sulfate proteoglycans in maintaining the proper structure of Purkinje axons in the cerebellum of adult rats. To this end, we examined the morphology and distribution of intracortical Purkinje neurites after intraparenchymal injection of chondroitinase ABC. Staining with the lectin Wisteria floribunda agglutinin or 2B6 antibodies showed that this treatment efficiently removed chondroitin sulfate proteoglycans from wide areas of the cerebellar cortex. In the same sites, there was a profuse outgrowth of terminal branches from the Purkinje infraganglionic plexus, which invaded the deeper regions of the granular layer. In contrast, myelinated axon segments were not affected and maintained their normal relationship with oligodendroglial sheaths. Purkinje axon sprouting was first evident at 4 d and increased further at 7 d after enzyme application. Within 42 d, the expression pattern of chondroitin sulfate proteoglycans gradually recovered, whereas axonal modifications progressively regressed. Our results show that, in the absence of injury or novel external stimuli, degradation of chondroitin sulfate proteoglycans is sufficient to induce Purkinje axon sprouting but not the formation of long-lasting synaptic contacts. Together with other growth-inhibitory molecules, such as myelin-associated proteins, chondroitin sulfate proteoglycans restrict structural plasticity of intact Purkinje axons to maintain normal wiring patterns in the adult cerebellar cortex.

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“…Plasminogen and tPA have functions varying from synaptic transmission (Hoffman et al, 1998; to synaptic plasticity (Baranes et al, 1998;Neuhoff et al, 1999). tPA knockout mice show deficiencies in long term potentiation (Baranes et al, 1998) and also show distorted and punctated mossy fibers (Wu et al, 2000).…”

Section: Fig 2 Tpa Knockout Mice Have Reduced Infarct Volumes (A)mentioning

confidence: 99%

The Neurotoxicity of Tissue Plasminogen Activator?

Kaur

Zhao

Klein

et al. 2004

J Cereb Blood Flow Metab

239

185

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Abstract:Tissue plasminogen activator (tPA), a fibrin specific activator for the conversion of plasminogen to plasmin, stimulates thrombolysis and rescues ischemic brain by restoring blood flow. However, emerging data suggests that under some conditions, both tPA and plasmin, which are broad spectrum protease enzymes, are potentially neurotoxic if they reach the extracellular space. Animal models suggest that in severe ischemia with injury to the blood brain barrier (BBB) there is injury attributed to the protease effects of this exogenous tPA. Besides clot lysis per se, tPA may have pleiotropic actions in the brain, including direct vasoactivity, cleaveage of the N-methyl-Daspartate (NMDA) NR1 subunit, amplification of intracellular Ca ++ conductance, and activation of other extracellular proteases from the matrix metalloproteinase (MMP) family, e.g. MMP-9. These effects may increase excitotoxicity, further damage the BBB, and worsen edema and cerebral hemorrhage. If tPA is effective and reverses ischemia promptly, the BBB remains intact and exogenous tPA remains within the vascular space. If tPA is ineffective and ischemia is prolonged, there is the risk that exogenous tPA will injure both the neurovascular unit and the brain. Methods of neuroprotection, which prevent tPA toxicity or additional mechanical means to open cerebral vessels, are now needed.

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The Tissue Plasminogen Activator (Tpa/Plasmin) Extracellular Proteolytic System Regulates Seizure-Induced Hippocampal Mossy Fiber Outgrowth through a Proteoglycan Substrate

Cited by 185 publications

References 46 publications

Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation

Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation

Degradation of Chondroitin Sulfate Proteoglycans Induces Sprouting of Intact Purkinje Axons in the Cerebellum of the Adult Rat

The Neurotoxicity of Tissue Plasminogen Activator?

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