The role of the tissue plasminogen activator/plasmin system in neuronal plasticity and anxiety-like behaviour

One remarkable feature of the brain is that it can adapt to cope with stressful experiences. While this is beneficial in most cases, severe stress can lead to abnormal brain adaptation and the development of anxiety disorders.
The nature of neuronal adaptation leading to abnormal anxiety is still unclear. In order to understand these processes mouse models of stress, anxiety and fear are often used. Using these models it has been shown that one brain region important for processing stress-related information and for anxiety is the amygdala. However, little is known about the molecular mechanisms that operate in this region to facilitate the development of anxiety disorders.
We have previously shown that a protein called tissue plasminogen activator (tPA) is present in the amygdala and it mediates stress-related neuronal adaptation. Mice in which the tPA gene has been disrupted do not show neuronal adaptation and anxiety in response to stress.
The mechanisms by which tPA facilitates stress-induced anxiety is not known. In this project we propose to elucidate these mechanisms by examining the role of molecules that interact with tPA in the amygdala during psychological stress. These studies will help develop more efficient therapies for anxiety disorders.

Experience-induced neuronal plasticity requires a coordinated sequence of events resulting in changes in neuronal connectivity and animal?s behavior. Tissue plasminogen activator (tPA) is a limbic system protease implicated in various forms of neuronal plasticity, including those underlying stress-induced anxiety (Pawlak et al, Nat Neurosci 2003; Matys, Pawlak et al., PNAS 2004; Pawlak et al, PNAS 2005). However, the mechanisms by which tPA facilitates emotional learning remain unclear. To elucidate these mechanisms we propose to explore the involvement of the major molecular interacting partners of tPA: membrane receptors (NMDA and low density lipoprotein receptor-related protein), latent growth factors (pro-brain-derived neurotrophic factor and hepatocyte growth factor) and zymogen proteases (plasminogen and matrix metaloproteases). We will examine the role of these molecules in the amygdala during psychological stress using genetic, cell biological, pharmacological and electrophysiological approaches. Finally, we will correlate these studies with behavioral experiments in mice deficient for critical components of the tPA system.