Role of the JAK/STAT pathway in 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 glutamate receptor, the NMDA receptor, which leads to alterations in the number of another class of glutamate receptor, the AMPA receptor, at synapses. We recently identified that the JAK2/STAT3 pathway is involved in LTD. This pathway is well known for regulating gene expression during inflammation or cell proliferation, for example. Dysregulation of this pathway can lead to auto-immune diseases or cancer and has also been linked recently to Alzheimer's disease. The aim of the proposed project is to find the mechanisms by which JAK2 and STAT3 are involved in LTD in the hippocampus, a brain region critically involved in learning and memory. Indeed, the way JAK2 is activated and how it leads to a reduction in AMPA receptor number at synapses remain to be defined. Furthermore, against expectation, we found that, during the first few hours after induction of LTD, the action of STAT3 is independent of gene regulation but involves one or more unknown targets in the cytoplasm that are important to identify. Since STAT3 translocates to the nucleus after LTD, it may nevertheless regulate the expression of genes that are important for the maintenance of LTD at later stages of the process. The present proposal aims at answering these and related questions in order to identify how this pathway is involved in LTD. We believe this project will lead to a better understanding of synaptic plasticity and the associated diseases but also bring more clues about the role of JAK2 and STAT3 in cell biology in general. This project could also potentially lead to the discovery of new JAK2 and STAT3 effectors which could be used as therapeutic targets. Indeed, these molecules have been targeted for the treatment of some auto-immune diseases (such as myelofibrosis and rheumatoid arthritis) and cancer (such as lymphomas). Clinical trials for JAK and STAT inhibitors are under way. However, the role of JAK and STAT is important for different physiological processes and the mediation of different cytokine receptors (e.g., Il-6, IL-12, Interferons). Therefore, a strong or complete inhibition of this pathway is not desirable and can lead to haematological disorders, dizziness and headaches. Finding new JAK2 or STAT3 effectors is a first step to extend our knowledge about this pathway in the brain which should help in the identification of new therapeutic targets for a range of disorders.

Synaptic plasticity is a process by which synapses alter the efficiency of transmission. The two main long-lasting forms of synaptic plasticity, termed LTP and LTD, involve alterations in the efficiency of transmission mediated by AMPA receptors (AMPAR). In the hippocampus, NMDA receptor-dependent synaptic plasticity is strongly implicated in learning and memory. LTD in the hippocampal CA1 region involves the activation of serine/threonine (ser/thr) protein phosphatases and a ser/thr kinase, GSK-3beta. We have recently identified that the tyrosine kinase JAK2 and its downstream effector, STAT3, are also involved in LTD. The JAK/STAT pathway is well known for regulating gene expression during inflammation or cell proliferation. Dysregulation of this pathway can lead to auto-immune diseases and cancer and has also been linked recently to Alzheimer's disease (AD). How this pathway is activated during LTD and how it leads to AMPAR removal from synapses remains to be identified. We plan to address these and related questions in this proposal: how is JAK2 activated and regulated during LTD and can it act on NMDA or AMPA receptors or any other synaptic proteins? Although STAT3 is a transcription factor we found that its role on LTD, during the first few hours, is independent of transcription. So what are its cytoplasmic effectors? We found that STAT3 translocates to the nucleus after LTD suggesting that transcriptional activity may be important for later stages of the process. So how might this regulation occur? Finally, could JAK2/STAT3 be a node of convergence between different forms of LTD triggered by other regulators such as cytokines or hormones? Answering these questions will not only lead to a better understanding of the mechanisms involved in LTD but will also give us a greater understanding of the role of JAK2 and STAT3 in general cellular function. Therefore, this project will be of of interest to both neuroscientists and non-neuroscientist alike.

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, for example, by the level of citations by fellow scientists. Thus, a review on NMDA receptor dependent LTP by the PI, co-authored with Tim Bliss, has been cited over 7,500 times.

Dysfunctioning of synaptic plasticity is believed to be central to many neurological and psychiatric disorders. An understanding of the normal function of JAK2 and STAT3 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 GSK3 inhibitors in the treatment of Alzheimer's disease and schizophrenia. Our work is likely to draw their attention to JAK2, STAT3 or one of their effector as a candidate molecule to target for these diseases, which have a huge economic and social burden in the UK. Since JAK2 and STAT3 dysregulation have been involved in pathologies such as auto-immune diseases and cancer, a lot of attention is already given to inhibitors of these molecules as treatment for these diseases. Several are already under clinical trials and one in particular, ruxolitinib, has been approved for the treatment of polycythemia vera and myelofibrosis, disorders where JAK2 is overactivated (gain-of-function mutations). However, inhibition of these molecules has undesirable secondary effects such as anemia, neutopenia, dizziness and headaches. Understanding how these molecules function in neurons and in the cell in general could therefore be of interest for all the pathologies where JAK2 and STAT3 are involved.
We will ensure that the pharmaceutical industry are aware of the research and its potential significance. The PI is on the Board of the Centre for Cognitive Neuroscience, a large consortium of academics and scientists at Eli Lilly. He also collaborates with/consults for various other Pharma. In a previous collaboration with Merz (Germany), he helped identify how an NMDA antagonist, memantine, could enhance synaptic plasticity that is now used as a treatment for Alzheimer's disease.

Information will be transferred via publication of the work in high impact journals, as well as through presentations at conferences. The discovery of the involvement of JAK2 and STAT3 in LTD has been published this year in Neuron and has already received over 5 citations including 2 in commentaries. It has also been the subject of a recent review targeting the general public and has been (and will be) presented at different conferences. Celine Nicolas has been invited to present her discovery at the BNA meeting in 2013 and at one of the prestigious Kavli Discusison Meetings of The Royal Society in 2013. Similar results are expected from this proposal.

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 where cognitive decline is a major concern.