Mechanisms of synaptic function and plasticity

Research in our group is aimed at understanding how nerve cells communicate with one another, and how this communication is changed by experience. Such changes are believed to be the basis for memory storage in the brain. To understand the mechanisms involved, we are combining optical and electrical recording methods to monitor activity at individual synapses the microscopic sites where one nerve cell contacts and communicates with another in living brain tissue. By introducing suitable fluorescent molecules into the nerve cells, we have revealed new mechanisms regulating synaptic levels of calcium, a key ion that controls release of neurotransmitters and many other important processes in nerve cells. We are now using genetic methods, by which variants of specific proteins are introduced into the nerve cell, to probe the role of these proteins in synaptic communication and memory. Computer modelling provides a theoretical framework for interpretation of our results.

Technical Summary

Our group studies the mechanisms of synaptic transmission and plasticity, particularly forms of long-lasting, activity-dependent plasticity that are the likely elementary mechanisms of memory storage in the brain. Our technical approach combines electrophysiological and optical imaging methods, including confocal and multiphoton-excitation microscopy, fast CCD imaging and use of fluorescent ion- and voltage-sensitive dyes. Thus, for example, by observing synaptically-evoked Ca2+ transients in individual presynaptic nerve terminals and postsynaptic dendritic spines in the hippocampus, we have identified previously unrecognised roles for Ca2+-induced Ca2+ release from internal stores at both sides of the synapse. Postsynaptic Ca2+ transients can be used to monitor transmission at individual excitatory synapses in living brain tissue; in this way we have recently demonstrated that long-term potentiation and depression (LTP and LTD) are expressed mainly by changes in reliability of transmission, and that these changes are graded and bidirectional. We are now expressing various mutant and fluorescent fusion proteins to probe the role of specific molecular pathways in synaptic function and plasticity. The results of these studies are used to constrain computational models embodying specific hypotheses of information storage mechanisms in brain. Besides adding to our understanding of fundamental aspects of brain function, this research programme has generated a new approach to high throughput screening for cognitive enhancing drugs.