Localization and Regulation of the Tissue Plasminogen Activator–Plasmin System in the Hippocampus

Sallés, Fernando J.; Strickland, Sidney

doi:10.1523/jneurosci.22-06-02125.2002

Cited by 145 publications

(123 citation statements)

References 52 publications

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“…tPA is highly expressed in the hippocampus, the region responsible for learning and memory (31)(32)(33). 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).…”

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.

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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...

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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.

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“…Urokinase plaminogen activator is an extracellular serine protease, which is expressed in most brain regions in the CNS [1,[43][44][45] and exerts its main enzymatic actions by converting inactive precursor plasminogen to the active protease plasmin [46][47][48] and by degrading certain components in extracellular matrix, such as laminin [47,[49][50][51][52][53]. The role of uPA for extracellular matrix degradation and dendritic spine dynamics has been well established [54,55].…”

Section: Discussionmentioning

confidence: 99%

Effects of urokinase-type plasminogen activator in the acquisition, expression and reinstatement of cocaine-induced conditioned-place preference

Bahí

Kusnecov

Dreyer

2008

Behavioural Brain Research

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a b s t r a c tCocaine and many other psychostimulants strongly induce urokinase-type plasminogen activator (uPA) expression in the mesolimbic dopaminergic pathway, which plays a major role in drug-mediated behavioral plasticity [Bahi A, Boyer F, Gumy C, Kafri T, Dreyer JL. In vivo gene delivery of urokinase-type plasminogen activator with regulatable lentivirus induces behavioral changes in chronic cocaine administration. Eur J Neurosci 2004;20:3473-88; Bahi A, Boyer F, Kafri T, Dreyer JL. Silencing urokinase in the ventral tegmental area in vivo induces changes in cocaine-induced hyperlocomotion. J Neurochem 2006;98:1619-31; Bahi A, Dreyer JL. Overexpression of plasminogen activators in the nucleus accumbens enhances cocaine-, amphetamine-and morphine-induced reward and behavioral sensitization. Genes Brain Behav 2007]. In this study, the role of mesolimbic dopamine (DA) pathways in the development of cocaine reward was examined by conditioned-place preference in rats with bilateral intra-accumbens injections of uPA-expressing lentiviral vectors. We show that overexpression of uPA in the Nac significantly augments cocaine-induced place preference. Furthermore, while this did not affect the ability of preference to be extinguished, reinstatement with a low dose of cocaine produced significantly greater preference to the cocaine-associated context. Once CPP had been established, and the preference extinguished, reinstatement induced by a priming dose of cocaine was facilitated by uPA. Inhibition of this serine protease expression using doxycycline abolished the augmented acquisition produced by overexpression of uPA but not the expression of the cocaine-induced CPP. When uPA is inhibited during the acquisition phase, animals no longer demonstrate place preference for the environment previously paired with cocaine. B428, a specific uPA inhibitor does not affect drug reinstatement after extinction if uPA has been activated during acquisition, a clear indication that uPA is involved in the acquisition phase of conditioned-place preference. Our results suggest that that increased uPA expression with repeated drug exposure produces conditions for enhanced acquisition of cocaine-induced CPP, indicating that cocaine-induced CPP and reinstatement may be dependent on active extracellular uPA.

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“…Brains were removed, postfixed, and immersed in 30% sucrose. After sectioning, slices were blocked (1% BSA, 5% goat serum, and 0.5% Triton X-100 in PBS) for 4 h at room temperature followed by incubation in primary antibody, which had been preabsorbed on tPA −/− tissue for 4 h at room temperature (37).…”

Section: Methodsmentioning

confidence: 99%

Tissue plasminogen activator is required for the development of fetal alcohol syndrome in mice

Noel

Norris

Strickland

2011

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

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Ethanol exposure during developmental synaptogenesis can lead to brain defects referred to as fetal alcohol syndrome (FAS), which can include mental health problems such as cognitive deficits and mental retardation. In FAS, widespread neuronal death and brain mass loss precedes behavioral and cognitive impairments in adulthood. Because tissue plasminogen activator (tPA) has been implicated in neurodegeneration, we examined whether it mediates FAS. Neonatal WT and tPA −/− mice were injected with ethanol to mimic FAS in humans. In WT mice, ethanol elicited caspase-3 activation, significant forebrain neurodegeneration, and decreased contextual fear conditioning in adults. However, tPA-deficient mice were protected from these neurotoxicities, and this protection could be abrogated by exogenous tPA. Selective pharmacological modulators of NMDA and GABA A receptor pathways revealed that the effects of tPA were mediated by the NR2B subunit of the NMDA receptor. This study identifies tPA as a critical signaling component in FAS.

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Localization and Regulation of the Tissue Plasminogen Activator–Plasmin System in the Hippocampus

Cited by 145 publications

References 52 publications

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

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

Effects of urokinase-type plasminogen activator in the acquisition, expression and reinstatement of cocaine-induced conditioned-place preference

Tissue plasminogen activator is required for the development of fetal alcohol syndrome in mice

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