A mouse brain cell’s ability to weaken its connections—a process called long-term depression—may depend on a specific set of receptors sitting on the *sending* side of the synapse, not the receiving side. This matters because the brain uses both strengthening (long-term potentiation) and weakening (long-term depression) of synapses to wire itself correctly during development and to store memories in adulthood. While scientists know that strengthening requires receptors on the receiving cell, the location and mechanism behind weakening remain unclear. This project tests whether weakening requires receptors on the *presynaptic* side, and whether they signal through ion flow or a different chemical pathway. If successful, this research will resolve a fundamental question about how the same receptor type produces opposite effects on synaptic strength. The work is primarily curiosity-driven fundamental science, but understanding these mechanisms could eventually illuminate what goes wrong in neurodevelopmental disorders like schizophrenia or autism, where synaptic pruning is thought to be disrupted, and in neurodegenerative diseases such as Alzheimer’s, where synapses are pathologically lost.
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Context For the correct wiring of neural connections during development, bidirectional synaptic plasticity is required. Such bidirectional plasticity has been most thoroughly studied in the hippocampus, which displays both synaptic long-term potentiation (LTP) and long-term depression (LTD). Synaptic potentiation is present throughout life and is important for learning and memory processes, whereas it is assumed that synaptic depression is developmentally regulated and more important early in life when an excess of synaptic connections is pruned away. It is thought that synaptic depression is the first step in this activity-dependent process of selective synapse elimination. Project challenge Both LTP and LTD require NMDA receptors for their induction. The challenge addressed by this project is to understand how the same type of receptor can mediate opposite changes in synaptic weights. Three main explanations have been proposed: (1) different NMDA receptor subunit composition coupled to different signalling cascades, (2) different presynaptic versus postsynaptic location of the NMDA receptors, or (3) ionotropic versus metabotropic mode of signalling of the NMDA receptor. In this project we will focus on receptor location and mode of NMDA receptor signalling for induction of LTD in the mouse hippocampus. Aims and objectives It is well established that the induction of hippocampal LTP requires activation of postsynaptic ionotropic NMDA receptors. The aim of the proposed work is to test the hypothesis that induction of hippocampal LTD instead requires activation of presynaptic NMDA receptors. To test this hypothesis, we will use a combination of electrophysiology, molecular techniques and pharmacological manipulations. The first objective is to establish the presynaptic versus postsynaptic location of NMDA receptors required for the induction of two forms of LTD at hippocampal CA3-CA1 synapses. The second objective is to investigate whether these NMDA receptors signal via an ionotropic or metabotropic mechanism. Potential applications and benefits Synaptic plasticity is important for cortical circuit refinement in the developing brain as well as for learning and memory processes in the adult brain. The underlying mechanisms are of fundamental interest to basic neuroscientists. In addition, these mechanisms may be involved in disorders where synaptic connectivity is altered (so-called “connectopathies”). Researchers have increasingly recognised how synaptic plasticity gone awry in children and teenagers could lay the foundation for neurodevelopmental disorders, such as schizophrenia or autism. It may also be the case that some of the same plasticity mechanisms that normally help refine brain wiring early in life contribute to later pathological synapse loss in Alzheimer’s disease and other neurodegenerative disorders. If so, synaptic plasticity mechanisms could be a therapeutic target.
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