The brain is made up of billions of neurons that connect via trillions of synapses, the chemical junction between two neurons. Proper development and regulation of these synapses is crucial for the proper functioning of the brain. Indeed, synaptic dysfunction is thought to be the primary basis of many brain diseases, including Alzheimer?s disease, schizophrenia, autism, epilepsy, addiction, and chronic pain. In the brain, the majority of synapses important for learning and memory are chemically stimulated by glutamate. Glutamate activates a specific protein known as the N-methyl-D-aspartate (NMDA) receptor that plays an essential role in proper brain development and synapse functioning. However, two fundamental properties of the NMDA receptor remain elusive; 1) why do NMDA receptors require two chemical signals, glutamate and glycine, for activation? And 2) how can NMDA receptors regulate both the strengthening and weakening of synapses during learning and memory? Understanding these two critical functions of NMDA receptors, in addition to contributing to our basic knowledge of neurobiology, may also point to a therapeutic strategy that will directly target and possibly even reverse the core synaptic changes that cause brain disease states such as addiction and chronic pain. The goal of this proposal is to understand how NMDA receptor co-agonism influences synaptic plasticity. The central hypothesis is that co-agonist site occupancy dictates the directionality of synaptic plasticity. Recent evidence by myself and others has shown that long-term depression (LTD) does not actually require ion flow through the NMDA receptor channel, but requires only glutamate binding. These results are contrary to the long-standing view that long-term potentiation (LTP) was due to rapid, large levels of calcium influx through the receptor, and LTD was mediated by low level, repetitive increases in calcium. Instead, these new results suggest that NMDA receptors invoke intracellular signaling solely due to conformational changes upon agonist binding. Building upon these new findings, I have developed a model that predicts a fundamental role of glycine/D-serine site occupancy as a direct regulator of the directionality of synaptic plasticity. This model allows for predictions that can be rigorously tested with pharmacological approaches in slice electrophysiology (Aim 1) and the single-cell genetic manipulations (Aim 2) regularly used in my laboratory. Validation of this model will open a new frontier of NMDA receptor and synapse biology that will have a significant impact on many areas of neuroscience and may lead to the development of novel approaches to modify synaptic plasticity for the treatment of neuropsychiatric diseases.

Public Health Relevance

Precise development and regulation of synapses, the chemical junctions between neurons in the brain, is crucial for the proper functioning of the brain. Thus, subtle dysfunction of synapses are thought to be the primary cause of many brain diseases, including Alzheimer?s disease, epilepsy, schizophrenia, and addiction. A specific protein known as the N-methyl-D-aspartate (NMDA) receptor has the unique ability mediate both the strengthening and weakening of synapses, and this proposal aims to understand this ability with the hope of developing therapeutic strategies to reverse the synaptic dysfunction in various psychiatric and neurologic diseases.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Nadler, Laurie S
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University of California Davis
Schools of Medicine
United States
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