Rapid, specific and active site-catalyzed effect of tissue-plasminogen activator on hippocampus-dependent learning in mice

Pawlak, Robert; Nagai, Nobuo; Urano, Tetsumei; Napiórkowska-Pawlak, Dorota; Ihara, Hayato; Takada, Yumiko; Collen, D.; Takada, Akikazu

doi:10.1016/s0306-4522(02)00166-5

Cited by 68 publications

(65 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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%

“…Several reports suggest that proteins primarily known for their role in coagulation and neurodegeneration are also important for central nervous system (CNS) function, including stress-induced alterations in learning and memory (Pawlak et al, 2002(Pawlak et al, ,2005Pang et al, 2004). For example, Pawlak et al (2005) have demonstrated that a stress-induced decrease in NMDA receptor expression is enhanced by plasmin expression.…”

Section: Introductionmentioning

confidence: 99%

“…Mice deficient in the precursor to plasmin, plasminogen or the enzyme that converts plasminogen to plasmin, tissue plasminogen activator (tPA), were protected from this decrement in NMDA receptor expression, as well as the cognitive decline associated with stress (Pawlak et al, 2005). tPA−/ − mice also showed deficits in hippocampal learning that were reversed by tPA administration (Pawlak et al, 2002). Both tPA −/− and plasminogen −/− mice showed deficits in conditioned reward (Nagai et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Almonte

Hamill

Chhatwal

et al. 2007

Neurobiology of Learning and Memory

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Almonte

Hamill

Chhatwal

et al. 2007

Neurobiology of Learning and Memory

View full text Add to dashboard Cite

show abstract

“…Normally, tPA is up-regulated in hippocampal neurons shortly after induction of LTP (34), but tPA Ϫ/Ϫ mice show a decreased late phase of LTP (24,35) and impaired learning in certain paradigms (35). In addition, overexpression or infusion of tPA into the hippocampus results in enhanced LTP and improved learning (36,37). These results indicate a role for tPA in neuronal plasticity and memory formation.…”

Section: Resultsmentioning

confidence: 99%

Modulation of NR2B-regulated contextual fear in the hippocampus by the tissue plasminogen activator system

Norris

Strickland

2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Contextual fear conditioning is regulated by the hippocampus, and NR2B, a subunit of the NMDA receptor (NR), is involved in this process. We show that acute stress modulates tissue plasminogen activator (tPA) activity in the hippocampus by inducing expression of its inhibitor, plasminogen activator inhibitor-1. Acute stress increases NR2B expression and ERK1/2 phosphorylation, a classical marker of postsynaptic plasticity, in the hippocampus. tPA forms a complex with NR2B and is necessary for binding NR2B to postsynaptic density-95, allowing for NR activation and membrane anchoring. Acute stress increases the interaction between NR2B and RACK-1, which is also dependent on tPA, further suggesting that tPA is an important factor in NMDA signaling and plasticity in the hippocampus. Finally, acutely stressed tPA ؊/؊ mice show a decrease in contextual fear conditioning compared with stressed WT mice. These results indicate that tPA is a key modulator in stabilizing the NR complex during stress and participates in changes in behavior and synaptic plasticity.fear conditioning ͉ NMDA receptor ͉ postsynaptic density-95 ͉ plasminogen activator inhibitor T he hippocampus and amygdala are responsible for regulating the body's responses to stress (1, 2). Stressful situations damage the hippocampus by inducing atrophy and delaying neurogenesis, which inhibits memory formation and consolidation (3-8). Furthermore, repeated stress impairs hippocampaldependent cognition and enhances amygdala-dependent unlearned fear and fear conditioning (7).Hippocampal-based anxiety and learned fear can be studied by using contextual fear conditioning. Contextual fear depends on hippocampal formation and the amygdala (9, 10) and specifically involves NMDA receptor (NR) signaling (11)(12)(13)(14). A disruption of contextual fear and deficits in long-term potentiation (LTP) are observed in mice with genetic or pharmacological alterations of NR subunits (15)(16)(17)(18)(19)(20). This process also involves changes in synaptic plasticity and NR2B signaling in the hippocampus (14,(20)(21)(22), although the mechanism is unclear.Tissue plasminogen activator (tPA) is a serine protease that is synthesized by and stored in neurons and is secreted during membrane depolarization (23-25). The activity of tPA is upregulated in the mouse amygdala after brief restraint stress (26). Amygdala-based behavioral experiments showed that stress prevented exploratory behaviors in WT mice but not in tPA Ϫ/Ϫ mice (26), indicating a critical role for tPA in regulating the amygdala stress response. However, the role of tPA during the stress response in the hippocampus has not been investigated. tPA may act through a variety of protein-protein interactions as well as via proteolysis. Plasminogen activator inhibitor-1 (PAI-1) is a key inhibitor of tPA activity in the CNS, and a tPA/PAI-1 complex may act as a signaling molecule. The NR is an attractive target for tPA and/or the tPA/PAI-1 complex because tPA interacts with NR subunits (27-29). NRs and tPA each play roles in LT...

show abstract

“…For example, focal application of tPA facilitates-whereas similar treatments with tPA inhibitors block-late-phase long-term potentiation in the hippocampus (13,14) and tPA-KO mice show impaired persistence of hippocampal long-term potentiation (28). At the same time, tPA-KO mice show deficits in long-term spatial memory tasks (29). Interestingly, tPA-KO mice also show impaired persistence of striatal long-term potentiation and long-term depression (30), suggesting a similar role for ECM in restricting synaptic plasticity in this structure.…”

Section: Discussionmentioning

confidence: 99%

Ventral striatal plasticity and spatial memory

Ferretti

Roullet

Sargolini

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Spatial memory formation is a dynamic process requiring a series of cellular and molecular steps, such as gene expression and protein translation, leading to morphological changes that have been envisaged as the structural bases for the engram. Despite the role suggested for medial temporal lobe plasticity in spatial memory, recent behavioral observations implicate specific components of the striatal complex in spatial information processing. However, the potential occurrence of neural plasticity within this structure after spatial learning has never been investigated. In this study we demonstrate that blockade of cAMP response element binding protein-induced transcription or inhibition of protein synthesis or extracellular proteolytic activity in the ventral striatum impairs longterm spatial memory. These findings demonstrate that, in the ventral striatum, similarly to what happens in the hippocampus, several key molecular events crucial for the expression of neural plasticity are required in the early stages of spatial memory formation. T he formation of long-term memories is believed to involve a dynamic process by which a labile memory is progressively converted into a more stable and potentially permanent trace. Evidence for such a time-dependent process comes from studies demonstrating that electroconvulsive shock produces amnesia only if delivered shortly after learning, whereas the same treatment is ineffective when delivered several hours later (1). Long-term memory is accompanied by changes in neuronal morphology and connectivity, and these alterations are thought to be essential for the stabile encoding of new information (2). This transformation has been suggested to depend upon plastic changes that involve a sequence of specific and coordinated cellular processes. These begin with neurotransmitter receptor activation that induces shortterm changes in synaptic efficacy based on receptor phosphorylation and trafficking (3, 4). Subsequently, alterations in gene expression and protein synthesis occur that are the basis for longterm structural modifications (5, 6).A key issue in the study of memory in vertebrates is the brain site at which these processes occur. Clinical evidence in humans suggests that structures within the medial temporal lobe (MTL) play a prominent role in long-term memories. MTL lesions induce profound deficits in the formation of long-lasting declarative memories while sparing the acquisition of nondeclarative memories such as visual-motor skills (7,8). Such findings suggest that the hippocampus might be an essential site where plasticity occurs in the initial steps of declarative memory stabilization. Accordingly, those molecular events thought to be crucial for the long-term encoding of memories such as regulation of gene expression and protein synthesis, as well as structural changes, have been described in the hippocampus after spatial learning (6, 9, 10).Recent experimental evidence, however, demonstrates that structures different from the hippocampus might also be involved in ...

show abstract

Rapid, specific and active site-catalyzed effect of tissue-plasminogen activator on hippocampus-dependent learning in mice

Cited by 68 publications

References 46 publications

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

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

Modulation of NR2B-regulated contextual fear in the hippocampus by the tissue plasminogen activator system

Ventral striatal plasticity and spatial memory

Contact Info

Product

Resources

About