Tissue Plasminogen Activator Contributes to the Late Phase of LTP and to Synaptic Growth in the Hippocampal Mossy Fiber Pathway

Baranes, Danny; Lederfein, Doron; Huang, Yan-You; Chen, Mary; Bailey, Craig H.; Kandel, Eric R.

doi:10.1016/s0896-6273(00)80597-8

Cited by 383 publications

(352 citation statements)

References 55 publications

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“…Furthermore, both PAR1 (Striggow et al, 2001), and NMDA receptor subunits (Ishii et al, 1993) are highly expressed in brain regions involved with emotional learning, including hippocampus and amygdala. These results it well with suggestions that serine proteases can impact learning (Baranes et al, 1998;Pawlak et al, 2002;Nagai et al, 2004Nagai et al, ,2006Pang et al, 2004;Pawlak et al, 2005), and may suggest that PAR1 is a substrate at which serine proteases such as plasmin exert their actions.…”

Section: Discussionsupporting

confidence: 86%

“…We have previously demonstrated a critical role for BDNF within the amygdala in the acquisition of emotional learning in vivo (Rattiner et al, 2004a,b;Chhatwal et al 2006), raising the possibility that protease-mediated activation of BDNF may partially underlie these effects. Studies of LTP suggested that removal of tPA, which converts plasminogen to plasmin, can decrease late phase LTP in hippocampal slices (Baranes et al, 1998). These data are consistent with the idea that serine proteases may regulate synaptic plasticity in the CNS.…”

Section: Introductionsupporting

confidence: 81%

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Learning and memory deficits in mice lacking protease activated receptor-1

Almonte

Hamill

Chhatwal

et al. 2007

Neurobiology of Learning and Memory

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The roles of serine proteases and protease activated receptors have been extensively studied in coagulation, wound healing, inflammation, and neurodegeneration. More recently, serine proteases have been suggested to influence synaptic plasticity. In this context, we examined the role of protease activated receptor 1 (PAR1), which is activated following proteolytic cleavage by thrombin and plasmin, in emotionally-motivated learning. We were particularly interested in PAR1 because its activation enhances the function of NMDA receptors, which are required for some forms of synaptic plasticity. We examined several baseline behavioral measures, including locomotor activity, expression of anxiety-like behavior, motor task acquisition, nociceptive responses, and startle responses in C57Bl/6 mice in which the PAR1 receptor has been genetically deleted. In addition, we evaluated learning and memory in these mice using two memory tasks, passive avoidance and cued fear-conditioning. Whereas locomotion, pain response, startle, and measures of baseline anxiety were largely unaffected by PAR1 removal, PAR1−/− animals showed significant deficits in a passive avoidance task and in cued fear conditioning. These data suggest that PAR1 may play an important role in emotionally-motivated learning.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionsupporting

confidence: 81%

Learning and memory deficits in mice lacking protease activated receptor-1

Almonte

Hamill

Chhatwal

et al. 2007

Neurobiology of Learning and Memory

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“…Many reports indicate an involvement of the tPA-plasmin system in synaptic plasticity and remodeling (Baranes et al, 1998;Fiumelli et al, 1999;Neuhoff et al, 1999), control of the direction of BDNF's functions (Martinowich et al, 2007), regulation of long-term potentiation (Pang et al, 2004), pathophysiology of mood disorders (Eskandari et al, 2005;Tsai, 2006) and stress-induced anxiety . The neurotrophic effects of lithium in stressinduced hippocampal atrophy and antidepressant effects of this drug in rodent models (Wood et al, 2004;O'Brien et al, 2004) suggest a critical role of BDNF in these lithium-induced actions (reviewed in Chuang, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Smad3/4 has a prominent role in regulating the expression of proteins involved in neuronal survival/death, differentiation, and plasticity (reviewed in Sanyal et al, 2004;Gomes et al, 2005). One of the Smad3/4-regulated protein targets is plasminogen activator inhibitor type-1 (PAI-1, also referred to as Serp1), which binds and inactivates tissue-type plasminogen activator (tPA), a multifaceted protein implicated in neurite outgrowth (Krystosek and Seeds, 1981), neuronal migration (Moonen et al, 1982;Seeds et al, 1999), learning (Qian et al, 1993;Seeds et al, 1995), excitotoxicity (Tsirka et al, 1995), synaptic plasticity (Baranes et al, 1998;Fiumelli et al, 1999;Neuhoff et al, 1999), stress response , and pathogenesis of mood disorders (Eskandari et al, 2005;Tsai, 2006). Using small interfering RNA (siRNA) and dominant negative mutants specific to GSK-3α and GSK-3β, we recently reported that GSK-3α inhibition causes an upregulation of Smad3/4-dependent transactivation and PAI-1 protein levels, while inhibition of GSK-3β induces a downregulation of Smad3/4 transactivation and PAI-1 expression (Liang and Chuang, 2006).…”

Section: Introductionmentioning

confidence: 99%

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Liang¹,

Wendland²,

Chuang³

2008

Molecular and Cellular Neuroscience

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Smad proteins are intracellular transducers for transforming growth factor-β (TGF-β signaling and play a critical role in differentiation, tissue repair and apoptosis of the central nervous system. Both TGF-β and its regulated gene, plasminogen activator inhibitor type-1 (PAI-1), have been implicated in the etiology and progression of neurodegenerative diseases and mood disorders. We previously reported that GSK-3β protein depletion suppresses Smad3/4-dependent gene transcription and causes a reduction in PAI-1 expression. Here, we provide evidence that lithium, the drug for the treatment and prophylaxis of bipolar disorder, inhibits Smad-dependent signaling by regulating cAMP-protein kinase A (PKA), AKT-glycogen synthase kinase-3β (GSK-3β), and CRE-dependent signaling pathways in neuron-enriched cerebral cortical cultures of rats. We demonstrate that lithium-induced activation of these pathways inhibits Smad3/4-dependent gene transcription through an increase in pCREB Ser133 protein levels, an enhanced interaction between pCREB Ser133 and p300/CBP, which causes Smad3/4-p300/CBP complex disruption and transcriptional suppression of Smad3/4-dependent genes. Therapeutic implications of our findings are discussed.

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“…It has been demonstrated that tPA has an important role in synaptic activity (Qian et al, 1993). Indeed, tPA is stored in synaptic terminals, and neuronal tPA is connected to events associated with the development of synaptic plasticity, such as motor learning (Seeds et al, 1995) and long-term potentiation (Baranes et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Tissue-Type Plasminogen Activator has a Neuroprotective Effect in the Ischemic Brain Mediated by Neuronal TNF-α

Haile

Echeverry

et al. 2011

J Cereb Blood Flow Metab

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Cerebral cortical neurons have a heightened sensitivity to hypoxia and their survival depends on their ability to accommodate to changes in the concentration of oxygen in their environment. Tissuetype plasminogen activator (tPA) is a serine proteinase that activates the zymogen plasminogen into plasmin. Hypoxia induces the release of tPA from cerebral cortical neurons, and it has been proposed that tPA mediates hypoxic and ischemic neuronal death. Here, we show that tPA is devoid of neurotoxic effects and instead is an endogenous neuroprotectant that renders neurons resistant to the effects of lethal hypoxia and ischemia. We present in vitro and in vivo evidence indicating that endogenous tPA and recombinant tPA induce the expression of neuronal tumor necrosis factor-a. This effect, mediated by plasmin and the N-methyl-D-aspartate receptor, leads to increased expression of the cyclin-dependent kinase inhibitor p21 and p21-mediated development of early hypoxic and ischemic tolerance.

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Tissue Plasminogen Activator Contributes to the Late Phase of LTP and to Synaptic Growth in the Hippocampal Mossy Fiber Pathway

Cited by 383 publications

References 55 publications

Learning and memory deficits in mice lacking protease activated receptor-1

Learning and memory deficits in mice lacking protease activated receptor-1

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Tissue-Type Plasminogen Activator has a Neuroprotective Effect in the Ischemic Brain Mediated by Neuronal TNF-α

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