Stable functionality in the nervous system is maintained despite the challenges associated with development, growth, experience, aging, and disease. This remarkable stability is controlled by potent and adaptive homeostatic signaling systems that sustain robust and reliable information transfer across synapses. Synapses are therefore critical substrates to achieve and maintain the homeostatic control of neural activity. Indeed, homeostatic synaptic plasticity is fundamental form of plasticity endowed at synapses in the central and peripheral nervous systems of invertebrates, rodents, and humans. Defects in homeostatic signaling contribute to the etiology of a variety of neurological diseases including epilepsy, Fragile X Syndrome, and neurodegeneration. However, the molecular mechanisms that induce and sustain homeostatic plasticity remain enigmatic. To understand synaptic dysfunction during disease states, we must first decipher the intercellular dialogue that controls homeostatic signaling. Our long-term goals are to define the mechanisms that achieve and maintain the homeostatic control of synaptic function in health and disease. Towards this end, we have pioneered forward genetic screens using electrophysiology that have discovered new genes and revealed fundamental mechanisms mediating homeostatic signaling at the Drosophila neuromuscular junction. At this model glutamatergic synapse, acute pharmacological inhibition or chronic genetic elimination of postsynaptic glutamate receptors (GluRs) triggers a retrograde signaling system in the postsynaptic compartment that precisely increases presynaptic neurotransmitter release to maintain stable synaptic strength. This process is referred to as Presynaptic Homeostatic Potentiation (PHP). Work from the Dickman lab and others have uncovered many presynaptic genes that converge on two key mechanisms that serve to increase neurotransmitter release and enable the expression of PHP. In addition, candidate retrograde signals have also been identified. In contrast to the emerging framework from which we now understand how enhanced presynaptic neurotransmitter release is controlled following PHP expression, almost nothing is known about the signaling system in the postsynaptic compartment that senses diminished GluR function and transforms this into tunable information transmitted to specific presynaptic compartments. Therefore, illuminating the nature of the postsynaptic induction mechanisms that initiate and maintain PHP will be the primary goal of this proposal. In this supplement, we propose to investigate the function of two newly identified postsynaptic genes, peflin and ALG2, in retrograde homeostatic signaling.

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 #
3R01NS091546-06S1
Application #
10062396
Study Section
Program Officer
Gubitz, Amelie
Project Start
2020-01-01
Project End
2021-12-31
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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Li, Xiling; Goel, Pragya; Wondolowski, Joyce et al. (2018) A Glutamate Homeostat Controls the Presynaptic Inhibition of Neurotransmitter Release. Cell Rep 23:1716-1727
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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