Nerve cells in the hippocampus strengthen or weaken their connections to store memories, and this project focuses on the weakening process—long-term depression (LTD)—which is far less understood than its counterpart, long-term potentiation (LTP). The brain’s ability to rewire its synapses, known as synaptic plasticity, is essential for learning and memory throughout life. While LTP has been heavily studied, the molecular machinery behind LTD remains poorly mapped. This matters because disruptions in both LTP and LTD are now linked to dementia, epilepsy, depression, and schizophrenia. The researchers have already found that a protein called GSK-3β, which is implicated in several brain disorders, plays a key role in LTD. They now aim to trace the full chain of molecular events—from calcium signals to receptor movements on the synapse—that trigger LTD in the hippocampus. This is fundamental science. It will not produce a drug or diagnostic tool tomorrow. But understanding how synapses weaken in a healthy brain is a prerequisite for figuring out why they weaken too much or too little in disease. Similar fundamental work on LTP decades ago reshaped how we think about memory storage and brain repair. A clearer picture of LTD could eventually point toward new targets for treating conditions where synaptic connections go awry.
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Synaptic plasticity is the process by which synapses can alter their efficiency of transmission; the two main forms are long-term potentiation (LTP) and long-term depression (LTD). The principal excitatory neurotransmitter in the brain, L-glutamate, exerts its physiological actions via three types of ionotropic receptors, named after the agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate, as well as a family of G-protein coupled, metabotropic glutamate receptors (mGluRs). Since the discovery that NMDA receptors (NMDARs) are the trigger for LTP at CA1 synapses in the hippocampus, and that they are involved in hippocampus-dependent learning and memory, it has become very evident that NMDAR-dependent LTP (NMDAR-LTP) is critical for a variety of cognitive processes. More recently, evidence has been accumulating for the importance of LTD, triggered by the activation of NMDARs or mGluRs, in various forms of learning and memory. These plastic processes are critical throughout life, from the connections made during development through to explicit forms of learning and memory into adulthood. Increasingly it is being realised that alterations in LTP and LTD contribute in various ways to a variety of neurological and psychiatric disorders, such as dementia, epilepsy, depression and schizophrenia. We and others have recently made molecular links between plasticity and disease, which suggests that dysregulation in synaptic plasticity may directly contribute to the aetiology of a number of neurological pathologies. For example, in the process of studying mechanisms of LTD in the hippocampus, we have recently identified key roles for a number of proteins that are linked to neuropathogies, including glycogen synthase kinase-3beta (GSK-3beta). We now plan to address several key unanswered questions concerning molecular mechanisms of NMDAR-LTD and mGluR-LTD in the hippocampus, with a focus on phosphorylation cascades, Ca2+ signalling and glutamate receptor trafficking. Based on extensive pilot data we plan to establish new components of molecular pathways underlying different forms of LTD, and to deduce precisely how induction of LTD, and the accompanying transient increase in cytosolic Ca2+, results in alterations in the synaptic expression of glutamate receptors. A key new development for our work will be the study of LTD in adult mice in vivo. We plan to establish how the signalling cascades that have been identified in simplified preparations operate in the intact animal. These findings will contribute to a fuller understanding of the molecular basis of major forms of synaptic plasticity in the brain, work that is directly relevant to a substantial number of major brain disorders
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