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.
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.
|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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