Regulating synapse form and function

Lead Research Organisation: MRC Cell Biology Unit

Abstract

Our nervous system relies on information flow across specialized points of intercellular contact called synapses. Synapses communicate by releasing chemical messengers known as neurotransmitters that travel across a narrow gap between cells to activate their receptors on the adjacent cell surface. Changes in the efficacy of such synaptic transmission by altering the neurotransmitter release process and/or the function of receptors are thought to underlie cognitive processes such as learning and memory. Furthermore, a physical change in the shape of synaptic connections might accompany formation of durable memories. However, little is known of how changes in synaptic efficacy and synapse shape are coordinated. Our research goal is to understand the role of structural organization of synapses in regulating the properties of synaptic transmission, and how the changes in synaptic efficacy, in turn regulate the shape and pattern of synaptic connections. As an experimental system, we use cultured rodent brain cells, which form networks of synaptic connections that are very similar to those found in intact brain. We monitor the efficacy of synaptic transmission by recording electrical impulses that result from synaptic communication, and we follow the changes in synaptic connections by direct visualization under a microscope.

Technical Summary

Synapse, a specialized zone of contact between two neurons, is the site at which communication takes place in the brain. Although neurons have reached the state of terminal differentiation, synapses continually form and are eliminated depending on the pattern of neural activity. The goal of our research is to delineate how experience in the form of synaptic activity shapes the structural organization of central synapses, and in turn, determines the connectivity pattern of neuronal networks. We hope to provide a molecular link for understanding processes that are thought to involve controlled changes in neuronal connectivity in the adult brain, such as memory consolidation. Our research program focuses on the structure-function relationship of synaptic junction at three levels. The first goal is to understand how synapse adhesion molecules and associated proteins modulate the efficacy of synaptic transmission. We focus on the mechanisms by which integrins and cadherin-catenin complex modify neurotransmitter release and postsynaptic receptor activity. Second, we investigate how synapse adhesion proteins, in turn, mediate activity-induced morphological synaptic plasticity. Finally, we address the nature of inter-synaptic organization with the premise that individual synapses are not strictly autonomous and that coordination between synapses plays an important role in shaping and maintaining functional neural networks. We study the axonal and dendritic mechanisms by which neighbouring synapses communicate and their synaptic strengths are regulated. As a main experimental system we use dissociated hippocampal neurons grown in culture. Cultured neurons form synaptic connections with physiological properties that are virtually indistinguishable from those found in intact tissue. They are well suited to our research since individual synaptic connections can be readily identified and their activity monitored. The research projects in our lab make use of the tools of cell biology and neuroscience. By combining electrophysiological and optical recordings with cellular and molecular intervention, we hope to delineate the mechanisms of activity-dependent modulation of neuronal connectivity in a simple cellular system.
 
Description EC FP7 Collaborative Project
Amount £280,000 (GBP)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 01/2010 
End 12/2013
 
Description International Joint Projects
Amount £12,000 (GBP)
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2009 
End 01/2011
 
Description Mechanisms of synapse regulation by tetraspanins and integrins 
Organisation National Research Council
Department Institute of Neuroscience (CNR-IN)
Country Italy 
Sector Academic/University 
PI Contribution exchange of complementary technical skills required for a common goal
Collaborator Contribution scientific collaboration
Impact Successful application to the Royal Society for an International Joint Projects grant
Start Year 2007
 
Description PhD studentship support 
Organisation Eisai Ltd
Department Eisai London Research Laboratories
Country United Kingdom 
Sector Private 
PI Contribution Investigation of a role for presenilins in neurotransmitter release
Collaborator Contribution PhD studentship support
Impact Training of a PhD student, and dissemination of the work carried out by the student at an international conference. Publication will be forthcoming.
Start Year 2006