Nervous systems from invertebrates to humans have shown remarkably resilient and adaptive abilities to maintain stable functionality despite challenges that may otherwise lead to suboptimal or uncontrolled activity. In each of these systems, perturbations to synaptic activity initially lead to corresponding alterations in synaptic strength. However, given sufficient time, nervous systems in these organisms adapt by modulating presynaptic release or postsynaptic neurotransmitter receptors to re-target previous levels of synaptic strength. This process, termed homeostatic synaptic plasticity, is thought to enable stable, yet flexible, synaptic activity and to play key roles in tuning neural function in health and disease. Yet there is a major gap in our knowledge of the molecular and cellular mechanisms that endow synapses with these extraordinary abilities. The long term goal of this proposal is to identify the genes and elucidate the mechanisms that achieve and maintain the homeostatic control of synaptic strength. To understand the principles governing homeostatic synaptic signaling, we will utilize the Drosophila neuromuscular junction, which has been established as a powerful genetic system to study this process. This proposal will use a combination of genetic analysis, electrophysiology, and imaging approaches to investigate the homeostatic mechanisms that enhance presynaptic release in response to a perturbation to postsynaptic neurotransmitter receptor function. In particular, three genes encoding neuronal transmembrane proteins have been identified that appear to function together in the presynaptic terminal to promote the calcium-dependent, homeostatic potentiation of synaptic transmission. Interestingly, these genes have been associated with epilepsy, schizophrenia, and bipolar disorder. The proposed experiments will first characterize these molecules in synaptic function and homeostatic plasticity. Confocal and super-resolution microscopy will then be utilized to reveal the subsynaptic localization and cellular activities of these proteins. Finally, complementary forward genetic screens are proposed to identify new genes that orchestrate homeostatic synaptic plasticity. Together, this work is expected to reveal new homeostatic genes and mechanisms that control the adaptive modulation of synaptic strength and provide a foundation from which to understand how transcellular homeostatic signaling systems more generally are established in the nervous system.

Public Health Relevance

Although homeostatic synaptic plasticity has been implicated in a variety of neurological and neuropsychiatric diseases including epilepsy, schizophrenia, autism, and Fragile X Syndrome, the molecular mechanisms remain poorly understood. This proposal seeks to characterize homeostatic genes associated with these diseases and reveal their functions in adaptive synaptic plasticity. This work will lead to greater understanding of ho dysfunction in synaptic plasticity may contribute to the etiology of neural disease and perhaps provide therapeutic targets for treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS091546-02
Application #
9002109
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Stewart, Randall R
Project Start
2015-02-01
Project End
2019-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
2
Fiscal Year
2016
Total Cost
$324,844
Indirect Cost
$127,969
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
Hartwig, Cortnie; Monis, William J; Chen, Xun et al. (2018) Neurodevelopmental disease mechanisms, primary cilia, and endosomes converge on the BLOC-1 and BORC complexes. Dev Neurobiol 78:311-330
Li, Xiling; Goel, Pragya; Chen, Catherine et al. (2018) Synapse-specific and compartmentalized expression of presynaptic homeostatic potentiation. Elife 7:
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
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
Goel, Pragya; Li, Xiling; Dickman, Dion (2017) Disparate Postsynaptic Induction Mechanisms Ultimately Converge to Drive the Retrograde Enhancement of Presynaptic Efficacy. Cell Rep 21:2339-2347
Perry, Sarah; Han, Yifu; Das, Anushka et al. (2017) Homeostatic plasticity can be induced and expressed to restore synaptic strength at neuromuscular junctions undergoing ALS-related degeneration. Hum Mol Genet 26:4153-4167
Hill, Alexis; Zheng, Xingguo; Li, Xiling et al. (2017) The Drosophila Postsynaptic DEG/ENaC Channel ppk29 Contributes to Excitatory Neurotransmission. J Neurosci 37:3171-3180
Chen, Xun; Ma, Wenpei; Zhang, Shixing et al. (2017) The BLOC-1 Subunit Pallidin Facilitates Activity-Dependent Synaptic Vesicle Recycling. eNeuro 4:

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