In situ zymographies from WT mouse hippocampi show decreased tPA activity in the mossy fiber pathway after 6 hrs restraint stress.

Anxiety is one of the most common mental illnesses in the United States, affecting nearly 20 million Americans each year. It is well documented that the amygdala and hippocampus are responsible for processing and interpreting stress signals as well as regulating the body's responses to stress. Repetitive stressful situations are damaging to many areas of the brains. For example, stress can cause shortening of dendrites in the prefrontal cortex and induce dendritic growth in the amygdala. Stress damages the hippocampus and prefrontal cortex as it induces atrophy and delays neurogenesis, which may impair memory formation and consolidation. Chronic restraint in mice and rats leads to the retraction and simplification of dendrites in the CA3 region of the hippocampus as well as the suppression of neurogenesis and cell survival in the dentate gyrus. Chronic stress impairs hippocampal-dependent cognition and enhances amygdala-dependent unlearned fear and fear conditioning.

Members of the Strickland Laboratory study tissue plasminogen activator (tPA), a serine protease that is synthesized by neurons. Since tPA is highly expressed in both the hippocampus and amygdala, the brain regions responsible for processing stressful stimuli, its activity was analyzed before and after inducing stress in mice. The Strickland laboratory recently showed that the activity of tPA is upregulated in the mouse amygdala after brief restraint stress. Furthermore, amygdala-based behavioral experiments showed that stress prevented exploratory behaviors in WT mice in the elevated plus maze task, but not in tPA-/- animals, indicating that there is a critical role for tPA in regulation of the biochemical and behavioral stress response in the mouse amygdala. However, the mechanism of tPA's involvement in the stress response has not been established nor has its involvement in the hippocampal response to stress been determined.

tPA may act through a variety of protein-protein interactions in addition to, or in lieu of, proteolysis. Plasminogen activator inhibitor 1 (PAI-1) is a key inhibitor of tPA activity in the central nervous system, and it is speculated that the tPA/PAI-1 complex may also act as a signaling molecule or receptor ligand. One molecule that is particularly attractive as a target for tPA and/or the tPA/PAI-1 complex is the NMDA-R. It is well-documented that tPA interacts with NMDA-R subunits, although the molecular details of these interactions have not been characterized. NMDA-Rs and tPA have each independently been shown to play roles in long term potentiation (LTP), synaptic plasticity, and the stress response. Erin Norris and Sidney Strickland have recently shown that tPA is a key regulator of contextual fear conditioning in the hippocampus via interactions with the NR2B subunit of the NMDA-R.

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