Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus
Open accessAbstract
Repeated stress can impair function in the hippocampus, a brain structure essential for learning and memory. Although behavioral evidence suggests that severe stress triggers cognitive impairment, as seen in major depression or posttraumatic stress disorder, little is known about the molecular mediators of these functional deficits in the hippocampus. We report here both pre- and postsynaptic effects of chronic stress, manifested as a reduction in the number of NMDA receptors, dendritic spines, and expression of growth-associated protein-43 in the cornu ammonis 1 region. Strikingly, the stress-induced decrease in NMDA receptors coincides spatially with sites of plasminogen activation, thereby predicting a role for tissue plasminogen activator (tPA) in this form of stress-induced plasticity. Consistent with this possibility, tPA-/- and plasminogen-/- mice are protected from stress-induced decrease in NMDA receptors and reduction in dendritic spines. At the behavioral level, these synaptic and molecular signatures of stress-induced plasticity are accompanied by impaired acquisition, but not retrieval, of hippocampal-dependent spatial learning, a deficit that is not exhibited by the tPA-/- and plasminogen-/- mice. These findings establish the tPA/plasmin system as an important mediator of the debilitating effects of prolonged stress on hippocampal function at multiple levels of neural organization.
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Chronic stress decreases spine synapse formation in hippocampus.
“but chronic stress decreases it in hippocampus (Pawlak et al., 2005)”
From Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators (2008) · cites this paper as Pawlak et al., 2005
Tissue plasminogen activator (tPA) is an extracellular protease and signalling molecule that is released with neural activity and is required for chronic stress-induced loss of spines and NMDA receptor subunits on CA1 neurons.
“Tissue plasminogen activator (tPA) is an extracellular protease and signalling molecule that is released with neural activity and is required for chronic stress-induced loss of spines and NMDA receptor subunits on CA1 neurons (Pawlak et al., 2005).”
From Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators (2008) · cites this paper as Pawlak et al., 2005
Tissue plasminogen activator is an extracellular protease and signaling molecule released with neural activity and is required for chronic stress-induced loss of spines and NMDA receptor subunits on CA1 neurons.
“Tissue plasminogen activator (tPA, see below) is an extracellular protease and signaling molecule that is released with neural activity and is required for chronic stress-induced loss of spines and NMDA receptor subunits on CA1 neurons.77”
From Protective and damaging effects of stress mediators: central role of the brain (2006) · cites this paper as [77]
Acute stress induces spine synapses in the CA1 region of hippocampus, and both acute and chronic stress increase spine synapse formation in amygdala, but chronic stress decreases it in hippocampus.
“Acute stress induces spine synapses in the CA1 region of hippocampus98 and both acute and chronic stress also increases spine synapse formation in amygdala,95-99 but chronic stress decreases it in hippocampus.77”
From Protective and damaging effects of stress mediators: central role of the brain (2006) · cites this paper as [77]
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- Authors
- Pawlak, R., Rao, B. S. S., Melchor, J. P., Chattarji, S., McEwen, B., & Strickland, S.
- Affiliations
- Tata Institute of Fundamental Research (IN)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-12-05
- Volume
- 102
- Issue
- 50
- Pages
- 18201-18206
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1312427
- OpenAlex
- W2140273147
- Cited by
- 223
- References
- 45
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 3 · 2023: 7 · 2022: 7 · 2021: 9 · 2020: 12 · 2019: 8 · 2018: 10 · 2017: 9 · 2016: 20 · 2015: 21 · 2014: 11 · 2013: 10 · 2012: 18
- FWCI
- 3.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Funders
- Wellcome Trust
- National Institute of Mental Health (MH-41256, R37MH041256, R01MH041256)
- National Institute of Neurological Disorders and Stroke (NS-38472, R01NS035704, NS35704, R01NS038472)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- tissue plasminogen activator, plasminogen, chronic stress, hippocampus, NMDA receptor, dendritic spines, growth-associated protein 43, cornu ammonis 1, spatial learning, cognitive impairment
- MeSH terms
- Analysis of Variance, Animals, Hippocampus, Immunohistochemistry, Plasminogen, Tissue Plasminogen Activator, Restraint, Physical, Stress, Physiological, Blotting, Western, Receptors, N-Methyl-D-Aspartate, Mice, Knockout, Maze Learning, Dendritic Spines, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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