The brain is astonishing in its complexity and capacity for change. It seems certain that the plasticity that drives our ability to learn and remember can only be meaningful in the context of otherwise stable, reproducible, and predictable baseline neural function. It is now clear that homeostatic signaling systems function throughout the central and peripheral nervous systems to stabilize neural function throughout life. As a consequence, it is widely believed that impaired or maladaptive homeostatic signaling will be directly relevant to the cause and progression of neurological diseases that include epilepsy, autism and neurodegeneration. However, despite widespread evidence for the homeostatic control of neural function throughout the animal kingdom and implicit relevance to disease and aging, very little is known about the underlying mechanisms. The field of homeostatic plasticity is wide open for exploration and the potential for transformative advancement in cellular and molecular neuroscience is tremendous. We are leading the rapidly emerging field of homeostatic plasticity, harnessing the power of unbiased model system genetics to identify and characterize fundamentally new cellular and molecular mechanisms of homeostatic signaling in the nervous system. Our experiments will define many of the first signaling pathways identified to participate in the homeostatic signaling systems that control presynaptic neurotransmitter release and intrinsic neural excitability. Our approaches have uncovered a novel activity of the innate immune signaling system, new trans-synaptic signaling pathways, novel calcium sensors, novel neuronal kinase signaling systems, new roles for the presynaptic endoplasmic reticulum and tangible links to neurological disease. As such, our data will provide a foundation for exploring the impact homeostatic plasticity in mammalian models of neurological disease including epilepsy, autism and neurodegeneration. Our data will also directly impact current theories and models of homeostatic signaling. Current theoretical models have captured widespread interest. Molecular insight will provide important new ideas and new constraints for the next generation of theoretical models of homeostatic plasticity, learning and memory.

Public Health Relevance

Our goal is to define the mechanisms that stabilize neural function throughout life. We have pioneered a sub- field of neuroscience, defining molecular mechanism that homeostatically control neurotransmission and neuronal firing properties. Our work is opening new avenues to treat aging and diseases of the brain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Unknown (R35)
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Special Emphasis Panel (ZNS1)
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Miller, Daniel L
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Harris, Nathan; Fetter, Richard D; Brasier, Daniel J et al. (2018) Molecular Interface of Neuronal Innate Immunity, Synaptic Vesicle Stabilization, and Presynaptic Homeostatic Plasticity. Neuron 100:1163-1179.e4
Ortega, Jennifer M; Genç, Özgür; Davis, Graeme W (2018) Molecular mechanisms that stabilize short term synaptic plasticity during presynaptic homeostatic plasticity. Elife 7:
Hauswirth, Anna G; Ford, Kevin J; Wang, Tingting et al. (2018) A postsynaptic PI3K-cII dependent signaling controller for presynaptic homeostatic plasticity. Elife 7:
Smart, Ashley D; Pache, Roland A; Thomsen, Nathan D et al. (2017) Engineering a light-activated caspase-3 for precise ablation of neurons in vivo. Proc Natl Acad Sci U S A 114:E8174-E8183
Orr, Brian O; Fetter, Richard D; Davis, Graeme W (2017) Retrograde semaphorin-plexin signalling drives homeostatic synaptic plasticity. Nature 550:109-113
Orr, Brian O; Gorczyca, David; Younger, Meg A et al. (2017) Composition and Control of a Deg/ENaC Channel during Presynaptic Homeostatic Plasticity. Cell Rep 20:1855-1866
Genç, Özgür; Dickman, Dion K; Ma, Wenpei et al. (2017) MCTP is an ER-resident calcium sensor that stabilizes synaptic transmission and homeostatic plasticity. Elife 6: