Absence of Tissue Plasminogen Activator Gene or Activity Impairs Mouse Cerebellar Motor Learning

Seeds, Nicholas W.; Basham, Mark E.; Ferguson, Jayne E.

doi:10.1523/jneurosci.23-19-07368.2003

Cited by 95 publications

(78 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, the vast majority of researchers have used zymography to detect in vivo changes in tPA activity in brain tissues; although others have used S2251 amidolytic assays to measure in vivo changes in tPA activity. 9,[26][27][28] In this study we show that this amidolytic assay, long-used as a sensitive and specific means to detect tPA in biological fluids such as plasma, 6,8 is also useful for determining in vivo changes in net tPA activity in mouse brain tissue when tested in the presence of its cofactor, fibrin.…”

Section: Discussionmentioning

confidence: 78%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 78%

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

View full text Add to dashboard Cite

show abstract

“…Hao et al, 2006). Hence, these results may suggest an important system and mechanism for the regulation of neurosecretory and catecholaminergic pathways in both central and peripheral nervous systems, with implications, for example, for t-PA/ plasminogen-dependent processes such as long-term potentiation, learning, and memory (Qian et al, 1993;Carmeliet et al, 1994;Frey et al, 1996;Huang et al, 1996;Baranes et al, 1998;Seeds et al, 2003;Pang et al, 2004), and excitotoxin-induced neuronal injury in the CNS (Tsirka et al, , 1997aChenLiu and Strickland, 1997), as well as for the regulation of key systemic cardiovascular and metabolic homeostatic physiological responses governed by sympathoadrenal and sympathoneural activity (Parmer et al, 2000;Jiang et al, 2001;Q. Jiang et al, 2002;X.…”

Section: Discussionmentioning

confidence: 86%

Cell-Surface Actin Binds Plasminogen and Modulates Neurotransmitter Release from Catecholaminergic Cells

Miles¹,

Andronicos²,

Baik³

et al. 2006

J. Neurosci.

View full text Add to dashboard Cite

An emerging area of research has documented a novel role for the plasminogen activation system in the regulation of neurotransmitter release. Prohormones, secreted by cells within the sympathoadrenal system, are processed by plasmin to bioactive peptides that feed back to inhibit secretagogue-stimulated release. Catecholaminergic cells of the sympathoadrenal system are prototypic prohormone-secreting cells. Processing of prohormones by plasmin is enhanced in the presence of catecholaminergic cells, and the enhancement requires binding of plasmin(ogen) to cellular receptors. Consequently, modulation of the local cellular fibrinolytic system of catecholaminergic cells results in substantial changes in catecholamine release. However, mechanisms for enhancing prohormone processing and cellsurface molecules mediating the enhancement on catecholaminergic cells have not been investigated. Here we show that plasminogen activation was enhanced Ͼ6.5-fold on catecholaminergic cells. Carboxypeptidase B treatment decreased cell-dependent plasminogen activation by ϳ90%, suggesting that the binding of plasminogen to proteins exposing C-terminal lysines on the cell surface is required to promote plasminogen activation. We identified catecholaminergic plasminogen receptors required for enhancing plasminogen activation, using a novel strategy combining targeted specific proteolysis using carboxypeptidase B with a proteomics approach using twodimensional gel electrophoresis, radioligand blotting, and tandem mass spectrometry. Two major plasminogen-binding proteins that exposed C-terminal lysines on the cell surface contained amino acid sequences corresponding to ␤/␥-actin. An anti-actin monoclonal antibody inhibited cell-dependent plasminogen activation and also enhanced nicotine-dependent catecholamine release. Our results suggest that cell-surface-expressed forms of actin bind plasminogen, thereby promoting plasminogen activation and increased prohormone processing leading to inhibition of neurotransmitter release.

show abstract

“…For example, tPA is involved in synaptic plasticity processes (Mataga et al, 2002), such as long-term potentiation (Huang et al, 1996;Pang et al, 2004) and long-term depression (Calabresi et al, 2000). Accordingly, tPA has been implicated in numerous behaviors, including various forms of learning and emotional behaviors (Seeds et al, 1995;Madani et al, 1999;Calabresi et al, 2000;Pawlak et al, 2002Pawlak et al, , 2003Seeds et al, 2003;Benchenane et al, 2007). Apart from these physiological functions, tPA was reported to influence neuronal, oligodendrocytic, and endothelial death/survival after excitotoxic, apoptotic, and/or inflammatory challenges (Chen and Strickland 1997;Wang et al, 1998;Nicole et al, 2001;Liu et al, 2004a;Liot et al, 2006;Correa et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…In the brain parenchyma, tPA is involved in physiological processes, including synaptic plasticity (Huang et al, 1996;Calabresi et al, 2000;Zhuo et al, 2000;Mataga et al, 2002;Pang et al, 2004) and behaviors (Seeds et al, 1995(Seeds et al, , 2003Madani et al, 1999;Pawlak et al, 2002Pawlak et al, , 2003Matys et al, 2004;Yamada et al, 2005). tPA also displays important roles in models of acute and chronic brain disorders, such as ischemic brain injury, seizure, and multiple sclerosis (Tsirka et al, 1995;Chen and Strickland 1997;Wang et al, 1998;Wu et al, 2000;Gveric et al, 2001;Lu et al, 2002;Liot et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

GluN2D Subunit-Containing NMDA Receptors Control Tissue Plasminogen Activator-Mediated Spatial Memory

et al. 2012

View full text Add to dashboard Cite

Tissue plasminogen activator (tPA) is a serine protease with pleiotropic actions in the CNS, such as synaptic plasticity and neuronal death. Some effects of tPA require its interaction with the GluN1 subunit of the NMDA receptor (NMDAR), leading to a potentiation of NMDAR signaling. We have reported previously that the pro-neurotoxic effect of tPA is mediated through GluN2D subunit-containing NMDARs. Thus, the aim of the present study was to determine whether GluN2D subunit-containing NMDARs drive tPA-mediated cognitive functions. To address this issue, a strategy of immunization designed to prevent the in vivo interaction of tPA with NMDARs and GluN2D-deficient mice were used in a set of behavioral tasks. Altogether, our data provide the first evidence that tPA influences spatial memory through its preferential interaction with GluN2D subunit-containing NMDARs.

show abstract

Absence of Tissue Plasminogen Activator Gene or Activity Impairs Mouse Cerebellar Motor Learning

Cited by 95 publications

References 50 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

Cell-Surface Actin Binds Plasminogen and Modulates Neurotransmitter Release from Catecholaminergic Cells

GluN2D Subunit-Containing NMDA Receptors Control Tissue Plasminogen Activator-Mediated Spatial Memory

Contact Info

Product

Resources

About