Homeostatic signaling systems operate at synapses to enable flexible yet stable information transfer in the nervous system. Defects in homeostatic signaling contribute to seizures, excitotoxicity, cognitive decline, and neurodegeneration. Although much has been learned in recent years about the expression mechanisms synapses employ to counteract perturbations to neurotransmission, the pathways that rapidly initiate and chronically maintain homeostatic signaling remains poorly understood. Here, we propose to determine the induction mechanisms mediating homeostatic synaptic plasticity using the Drosophila neuromuscular junction as a unique and powerful model system. At this glutamatergic synapse, pharmacologic or genetic disruption to postsynaptic neurotransmitter receptors triggers a retrograde signaling system that leads to a compensatory increase in presynaptic glutamate release to maintain stable synaptic strength, referred to as presynaptic homeostatic potentiation (PHP). This process parallels similar phenomena observed in a variety of other organisms, including mammalian central synapses. We have recently discovered an E3 ubiquitin ligase adaptor that targets substrates in the postsynaptic compartment and enables retrograde homeostatic signaling. We propose to first identify and characterize postsynaptic targets of the homeostatic signaling system. Preliminary data suggests a key component of the postsynaptic density is necessary for retrograde homeostatic signaling. Next, we will define the induction mechanisms mediating the chronic expression of PHP and determine the role of CaMKII in this process. Finally, we will interrogate the pharmacological induction of PHP and test a hypothesis that trans-synaptic complexes mediate rapid retrograde homeostatic signaling. These studies will leverage a synergistic combination of molecular genetic, electrophysiological, and innovative functional imaging approaches at confocal, super resolution, and ultrastructural levels to determine the induction mechanisms that initiate and maintain retrograde homeostatic signaling. Together, these experiments will advance our understanding of the fundamental mechanisms that endow synapses with the capacity to sense perturbations to neurotransmission and adaptively modulate synaptic function to stabilize information transfer in the nervous system.

Public Health Relevance

Defects in homeostatic signaling at synapses are associated with a variety of neurological and neuropsychiatric diseases including epilepsy, autism, schizophrenia, Fragile X Syndrome, ALS, and Alzheimer's Disease. However, the mechanisms that ensure stable synaptic strength remain poorly understood. This proposal seeks to reveal fundamental mechanisms that initiate and maintain homeostatic signaling at synapses, insights that are necessary for understanding disease etiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS091546-06
Application #
9867481
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Gubitz, Amelie
Project Start
2015-02-01
Project End
2024-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Southern California
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Goel, Pragya; Dickman, Dion (2018) Distinct homeostatic modulations stabilize reduced postsynaptic receptivity in response to presynaptic DLK signaling. Nat Commun 9:1856
Chen, Xun; Ma, Wenpei; Zhang, Shixing et al. (2017) The BLOC-1 Subunit Pallidin Facilitates Activity-Dependent Synaptic Vesicle Recycling. eNeuro 4:
Kiragasi, Beril; Wondolowski, Joyce; Li, Yan et al. (2017) A Presynaptic Glutamate Receptor Subunit Confers Robustness to Neurotransmission and Homeostatic Potentiation. Cell Rep 19:2694-2706
Kikuma, Koto; Li, Xiling; Kim, Daniel et al. (2017) Extended Synaptotagmin Localizes to Presynaptic ER and Promotes Neurotransmission and Synaptic Growth in Drosophila. Genetics 207:993-1006
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:
Perry, Sarah; Kiragasi, Beril; Dickman, Dion et al. (2017) The Role of Histone Deacetylase 6 in Synaptic Plasticity and Memory. Cell Rep 18:1337-1345
Chen, Xun; Dickman, Dion (2017) Development of a tissue-specific ribosome profiling approach in Drosophila enables genome-wide evaluation of translational adaptations. PLoS Genet 13:e1007117

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