Mechanisms of NMDA receptor-dependent LTP and LTD in the hippocampus.

The human brain contains an enormous network of neurons which communicate via specialised connections known as synapses. Synapses are fundamental to brain function but they are not permanently fixed, instead synapses are made and lost throughout life in response to changes in brain activity. In addition, the strength of a synapse can be modified to make the connection between neurons more or less effective. This process, known as synaptic plasticity, enables the activity of neuronal networks to be altered by experience. Synaptic plasticity is therefore believed to underlie our ability to learn and remember. The mechanisms of synaptic plasticity have been extensively studied in rodent hippocampus, a brain region essential for memory formation. The proposed research will investigate one form of synaptic plasticity, long-term potentiation, in rat hippocampal neurons. We will investigate the changes that occur to strengthen synapses during long-term potentiation, and how these changes actually happen. The results will increase our understanding of how changes in synaptic plasticity relate to changes in neuronal function and learning processes.

Synaptic plasticity is the process by which synapses can alter their efficiency of transmission. There are two main long-lasting forms of synaptic plasticity termed long-term potentiation (LTP) and long-term depression (LTD). Most forms of LTP, and many forms of LTD, are triggered by the synaptic activation of NMDA receptors (NMDARs) and subsequently involve alterations in the efficiency of transmission mediated by AMPA receptors (AMPARs). While significant progress has been made in understanding synaptic plasticity, there are still large gaps in our knowledge, particularly the mechanisms by which activation of NMDARs leads to alterations in the functioning of AMPARs. In the current proposal we will utilise an integrated multidisciplinary approach, which will combine extracellular and whole-cell recording, two-photon confocal imaging and uncaging experiments, pharmacology, biochemistry & molecular biology and neuronal modelling. By using rat hippocampal brain slices and cultures we shall investigate four main areas. We shall build on our previous work characterising developmental alterations in the expression mechanisms of LTP, which showed that changes in probability of glutamate release, AMPAR single channel conductance, and AMPAR number are involved in LTP expression at different ages. Importantly in this section we shall investigate LTP expression mechanisms in adult animals, which have been largely ignored until now. We shall determine how AMPAR number and subunit composition at the cell surface is controlled during LTP and LTD. By studying proteins that interact with AMPARs and are important for their trafficking and surface expression we aim to identify the precise role of these proteins in synaptic plasticity. In addition, we will make use of fluorescently tagged AMPAR subunits to monitor their surface expression and real time movement into and out of synapses during synaptic plasticity. Finally, we will examine the signalling cascades, in particular the role of protein kinases and phosphatases, which regulate these protein interactions and thus AMPAR trafficking. These studies will address several outstanding issues of LTP and LTD.