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

Lead Research Organisation: University of Leicester
Department Name: Cell Physiology and Pharmacology

Abstract

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.

Technical Summary

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.

Publications

10 25 50
 
Description European Commission - expert evaluator
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
Impact I was invited as an expert to assist the European Commission with evaluation of grant proposals in my area of expertise.
 
Description Training of researchers
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Creation of the website increased the awareness of medical students regarding neuroscience research. Several students joined my laboratory since to conduct research in this area.
 
Description Bangalore group 
Organisation Tata Institute of Fundamental Research
Country India 
Sector Public 
PI Contribution We have contributed to the discovery of the role of the tissue plasminogen activator in stress-induced dendritic spine plasticity in the amygdala
Impact 17049177 Bennur, S (Jan, 2007) Stress-induced spine loss in the medial amygdala is mediated by tissue-plasminogen activator., Neuroscience 144, 1, 8-16
Start Year 2006
 
Description New York group 
Organisation Rockefeller University
Country United States 
Sector Academic/University 
PI Contribution We contributed both intellectually and experimentally into studies on the role of the tPA/plasmin/laminin system in stress-induced cell death.
Collaborator Contribution Contributed intellectually and experimentally into our studies on the role of the tPA/plasmin/laminin system in stress-induced cell death.
Impact Publications PubMedID 19114596 and 19577227
Start Year 2007
 
Description Website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact We have created a website to inform the wide public of our activities. www.pawlaklab.com

It contributed to the general public awareness of neuroscience research. Since then several medical students from our University joined my laboratory to conduct research in this area.
Year(s) Of Engagement Activity 2007,2008,2009