In this grant, we have the potential to bridge two fields of investigation: innate immune signaling in the nervous system and the homeostatic control of synaptic transmission. The innate immune system is evolutionarily conserved in all animals. Recent work has revealed that innate immune signaling participates in neural development, plasticity and disease. This previous work includes evidence for the function of the C1q component of the complement cascade during synapse elimination, the function of Toll receptors in learning and memory, and the function of NFkB/Rel transcription factors in learning- related plasticity. In this grant, we identify a novel role for innate immune signaling in the nervous system. Specifically, we show that an innate immune receptor (PGRP-LC) and the downstream innate immune signaling cascade (the IMD signaling cascade) are required for homeostatic synaptic plasticity. The receptor appears to function at the presynaptic nerve terminal to induce two downstream effects: 1) the local homeostatic modulation of presynaptic neurotransmitter release and 2) the transcription-dependent maintenance of homeostatic plasticity. Our experiments will explore this possibility in molecular and genetic detail. Our findings may be broadly relevant for our understanding how neural function is stabilized throughout development, during aging and in the context of disease. More specifically, impaired homeostatic plasticity is believed to contribute to diverse neurological diseases including epilepsy, autism spectrum disorders, and anxiety. Our preliminary data and proposed experiments may also document a novel function for an innate immune signaling system that has never before been studied in the nervous system. Thus, our data may be significant at several levels, with implications for our understanding and treatment of diverse neurological diseases.

Public Health Relevance

In this grant, we have the potential to bridge two fields of investigation: innate immune signaling and the homeostatic control of neural function. The innate immune system is evolutionarily conserved in all animals. We have discovered that an innate immune receptor, never before studied in the nervous system of any organism, and the downstream signaling system, are necessary for the homeostatic stabilization of neural function. Impaired homeostatic stabilization of neural function is widely believed to be involved in neurological disorders that range from autism-spectrum disorders to epilepsy. As such, our insights and experiments could have broad clinical relevance.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Talley, Edmund M
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Harris, Nathan; Braiser, Daniel J; Dickman, Dion K et al. (2015) The Innate Immune Receptor PGRP-LC Controls Presynaptic Homeostatic Plasticity. Neuron 88:1157-64
Müller, Martin; Genç, Özgür; Davis, Graeme W (2015) RIM-binding protein links synaptic homeostasis to the stabilization and replenishment of high release probability vesicles. Neuron 85:1056-69
Parrish, Jay Z; Kim, Charles C; Tang, Lamont et al. (2014) Krüppel mediates the selective rebalancing of ion channel expression. Neuron 82:537-44
Wang, Tingting; Hauswirth, Anna G; Tong, Amy et al. (2014) Endostatin is a trans-synaptic signal for homeostatic synaptic plasticity. Neuron 83:616-29
Davis, Graeme W (2013) Homeostatic signaling and the stabilization of neural function. Neuron 80:718-28
Müller, Martin; Davis, Graeme W (2012) Transsynaptic control of presynaptic Ca²⁺ influx achieves homeostatic potentiation of neurotransmitter release. Curr Biol 22:1102-8
Graf, Ethan R; Heerssen, Heather M; Wright, Christina M et al. (2011) Stathmin is required for stability of the Drosophila neuromuscular junction. J Neurosci 31:15026-34
Keller, Lani C; Cheng, Ling; Locke, Cody J et al. (2011) Glial-derived prodegenerative signaling in the Drosophila neuromuscular system. Neuron 72:760-75
Cheng, Ling; Locke, Cody; Davis, Graeme W (2011) S6 kinase localizes to the presynaptic active zone and functions with PDK1 to control synapse development. J Cell Biol 194:921-35
Arber, Silvia; Davis, Graeme (2011) Developmental neuroscience. Curr Opin Neurobiol 21:1-4