The remarkable information processing capacity of neurons in the mammalian brain stems from the dense network of synaptic connections they receive and the ability of these synapses to change with experience. However, the constellation of synaptic changes thought to underlie learning and memory (""""""""Hebbian"""""""" plasticity) can also produce instability of activity within neural circuits, leading to a potential host of debilitating outcomes ranging from mental retardation to epilepsy. Work over the last decade has suggested that """"""""homeostatic"""""""" forms of synaptic plasticity can promote long-term stability within neuronal networks by offsetting potentially destabilizing levels of synaptic activity through compensatory increases or decreases in synaptic strength. While this idea has generated wide interest in the field, we still lack a clear picture of how these compensatory changes are implemented at synapses and how they work in concert with Hebbian synaptic modifications. Recent work has challenged the picture provided by initial accounts that homeostatic compensation at central synapses as an intrinsically slow and cell-wide form of plasticity. We now propose the hypothesis that homeostatic synaptic plasticity is not defined by a unitary global process, but rather describes a family of compensatory mechanisms, a subset of which interact locally at synapses with processes important for information storage. This hypothesis will be tested in three specific aims, by examining: whether unique features of synaptic/neuronal activity drive distinct forms of synaptic compensation (Aim 1);whether compartmentalized biochemical processing in neurons mediates distinct aspects of homeostatic plasticity (Aim 2);and whether local mechanisms of homeostatic compensation interact with Hebbian synaptic plasticity at the same set of synaptic inputs (Aim 3). Since this project centers around a class of processes that are fundamental to basic neuron function, its implications are likely to broad, informing aspects of neuron signaling, development, and the devastating neurological disorders that have been linked with homeostatic plasticity, such as epilepsy. This project will also inform many basic science issues related to our understanding of learning and memory, such as the role of localized protein synthesis and degradation in synaptic plasticity and how such Hebbian synaptic modifications can endure in the face of compensatory mechanisms that would otherwise reverse them.

Public Health Relevance

Our ability to learn and remember is thought to involve specific changes in the network of synaptic connections in the brain;however, synaptic changes thought to underlie learning and memory can also produce instability of activity within neural circuits, leading to a host of debilitating outcomes ranging from mental retardation to epilepsy. Work over the last decade has suggested that a different class of synaptic modification - homeostatic synaptic plasticity - promotes compensatory changes in the strength of synapses to offset destabilizing levels of activity within neuronal networks and recent evidence has linked altered regulation of homeostatic plasticity with neurological dysfunction. However, the traditional viewpoint has been that these homeostatic mechanisms act on the neuron as a whole, rather than at the level of individual synapses, and therefore do not interact with mechanisms important for learning and memory storage. Recent evidence has challenged this view prompting us to propose and test the hypothesis that neurons are not limited to a single global compensation mechanism to promote network stability, but can rather draw from a family of mechanistically-distinct processes, some of which act locally at synapses and can interact with mechanisms important for information processing and storage.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Asanuma, Chiiko
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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