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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS059867-07
Application #
8689182
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Talley, Edmund M
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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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
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