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Localization and regulation of the tissue plasminogen activator-plasmin system in the hippocampus
Fernando J Salles1, Sidney Strickland
1Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, New York 10021, USA. fsalles@cogentneuroscience.com
Abstract:
The extracellular protease cascade of tissue plasminogen activator (tPA) and plasminogen has been implicated in neuronal plasticity and degeneration. We show here that unstimulated expression of tPA in the mouse hippocampus is concentrated in the mossy fiber pathway, with little or no expression within the perforant path, the Schaffer collaterals, or neuronal cell bodies. tPA protein is also expressed in vascular endothelial cells throughout the brain parenchyma. Four hours after excitotoxic injury, tPA protein is transiently induced within CA1 pyramidal neurons. The induced CA1 tPA is localized to neurons that survive the injury and is enzymatically active. Within the mossy fiber pathway, injury resulted in decreased tPA protein. In contrast, mossy fiber tPA activity displayed a biphasic character: transient increase at 8 hr, then a decrease by 24 hr after injury. Analysis of plasminogen activator inhibitor-1 (PAI-1) expression showed that PAI-1 antigen is upregulated by 24 hr and could account for the tPA activity downregulation seen at this time point. Plasminogen immunohistochemistry suggested an increase within the mossy fiber pathway after injury. Finally, hippocampal tPA expression among various mammalian species was strikingly different. These results indicate a complex control of tPA protein and enzymatic activity in the hippocampus that may help regulate neuronal plasticity.
Insights
Tissue plasminogen activator (tPA) expression in the hippocampus changes after injury, with increased activity in surviving neurons and complex regulation in mossy fibers. This suggests tPA plays a role in neuronal plasticity and response to excitotoxic damage.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- The tissue plasminogen activator (tPA) and plasminogen system is involved in neuronal plasticity and degeneration.
- Understanding tPA regulation in the hippocampus is crucial for studying neurological conditions.
Purpose of the Study:
- To investigate the expression and activity of tPA in the mouse hippocampus following excitotoxic injury.
- To explore the role of tPA and its regulators in neuronal plasticity and injury response.
Main Methods:
- Immunohistochemistry to detect tPA, plasminogen, and plasminogen activator inhibitor-1 (PAI-1) protein.
- Analysis of tPA activity in specific hippocampal pathways (mossy fiber, CA1 pyramidal neurons).
- Comparative analysis of hippocampal tPA expression across mammalian species.
Main Results:
- Unstimulated tPA is concentrated in the mossy fiber pathway and vascular endothelial cells, with minimal expression elsewhere.
- Excitotoxic injury transiently induces active tPA in surviving CA1 pyramidal neurons.
- Mossy fiber tPA protein decreases post-injury, while its activity shows a biphasic response (increase then decrease).
- PAI-1 upregulation at 24 hours correlates with decreased tPA activity, and plasminogen increases in the mossy fiber pathway.
Conclusions:
- Hippocampal tPA expression and activity are complexly regulated, particularly after excitotoxic injury.
- Induced tPA in surviving neurons and altered mossy fiber activity suggest a role in neuronal plasticity.
- Species-specific differences in hippocampal tPA expression highlight evolutionary adaptations.
