The signalling pathways involved in NMDA receptor-dependent LTD

Information storage in the brain depends on changes in the efficiency by which nerve cells (neurons) communicate. This occurs at specialised structures (synapses) via the release of a chemical neurotransmitter and its detection by receptor proteins, a process called synaptic transmission. The strength of this communication can be increased or decreased, depending on the patterns of synaptic activation, i.e. synaptic plasticity. In general, synaptic transmission can be increased by the process known as long-term potentiation (LTP) or decreased by the process known as long-term depression (LTD). The best established forms of synaptic plasticity involve the activation of one class of L-glutamate receptor, the NMDA receptor, which leads to alterations in the number of another class of glutamate receptor, the AMPA receptor, at synapses. The aim of the proposed project is to find the mechanisms by which NMDA receptor activation leads to a decrease in AMPA receptor transmission during LTD in the hippocampus, a brain region critically involved in learning and memory. We have recently discovered two proteins that appear to play a central role in this process. The purpose of this project is to identify how these proteins are involved in this important form of synaptic plasticity.

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). NMDA receptor-dependent synaptic plasticity involves alterations in the efficiency of transmission mediated by AMPA receptors and in the hippocampus, NMDA receptor-dependent synaptic plasticity is strongly implicated in learning and memory. LTD in the hippocampal CA1 region classically involves protein phosphatase activation. However, we have recently investigated the potential role of the protein kinases (PK) in LTD. We found that, from over 60 PKs tested, two are involved in this process. We confirmed our previous work which identified a role for glycogen synthase kinase-3 (GSK-3) and discovered a role for a member of the Janus kinase (JAK) family. GSK-3 was previously found to be activated by a phosphatase cascade (PP2B/PP1) during LTD. However, nothing is known concerning the mechanism by which it regulates AMPA receptor transmission during LTD. The objective of the proposed project is now to find how JAK is activated during LTD and how GSK-3 and JAK lead to AMPA receptor internalisation during LTD. We first plan to find which isoform of JAK is involved in LTD and how it is activated. We will then focus on finding the targets of JAK and GSK-3, using different approaches comprising biochemistry, proteomics and electrophysiology on acute or organotypic cultured slices, as appropriate. This project should greatly increase our knowledge of the signalling pathways involved in LTD, from NMDA receptor activation to AMPA receptor internalisation.

It is extremely likely that this research will have a wide reaching impact on the scientific community. This is because the basic mechanisms of synaptic plasticity, and in particular the NMDA receptor dependent forms of LTP and LTD, are widely believed to be critically involved in information storage in the brain. In the hippocampus, where this work is to be carried out, LTP and LTD are strongly linked to explicit forms of learning and memory, but similar mechanisms also seem to mediate synaptic plasticity throughout the brain. The general impact of such work can be seen by, for example, the level of citations by fellow scientists. For example a review on NMDA receptor dependent LTP by the PI, co-authored with Tim Bliss, has been cited over 5,000 times. Whilst this work focuses on the physiological mechanisms of synaptic plasticity, it is noteworthy that dysfunctioning of synaptic plasticity is believed to be central to many neurological and psychiatric disorders. An understanding of the normal function of GSK-3 and JAK in synaptic plasticity will be very informative for the pharmaceutical industry in developing new therapeutic strategies for such conditions. For instance, there is already a huge interest in the therapeutic potential of GSK-3 inhibitors in the treatment of Alzheimer's disease and schizophrenia. Our work is likely to provide basic information about potentially more specific targets (e.g. down-stream effectors of GSK-3) and is likely to draw their attention to JAK as a candidate molecule to target for these diseases, which have a huge economic and social burden in the UK. Information will be transferred via publication of the work in high impact journals, as well as through presentations at conferences etc. For example, our first study with GSK-3 and LTD was recently published in Neuron and has already received over 40 citations. In addition, the PI has contacts with senior scientists in major Pharma, including Eli Lilly (Erl Wood), GSK and Astra Zeneca. The impact of the research will happen immediately, with respect to how it will inform the scientific community, since the PI and his team regularly present their work at scientific congresses. The work will reach a large scientific audience since the PI is often asked to give Plenary lectures at major congresses. In terms of new therapeutics, the time-scale will be much longer, due to the lead time for target validation and drug development. Since, however, the work is addressing the fundamental mechanisms of how our brain stores information the long-term benefits are potentially very wide reaching, particularly in an aging society. It is, of course, impossible to ensure that Pharma will benefit from our research. We can only make sure that they are aware of the research and its potential significance. The same applies equally to any potential user of the information. Our track record of engaging with Pharma is, however, very good. The PI is on the Board of the Centre for Cognitive Neuroscience, a large consortium of academics and scientists at Eli Lilly, based at Erl Wood (Surrey). He also collaborates with / consults for various other Pharma, including GSK and Astra Zeneca. In a previous collaboration with Merz (Germany), he helped identify how an NMDA antagonist (memantine) could enhance synaptic plasticity (which at first might appear paradoxical). This helped Merz get approval for memantine in the treatment of Alzheimer's disease.