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Principal Investigator: DION KAI DICKMAN
Organization: UNIVERSITY OF SOUTHERN CALIFORNIA
Fiscal Year: 2024
Award: $348,898
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <AD dementia><ASD><Acute><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Amino Acids><Autism><Autistic Disorder><Biologic Models><Biological Models><C-terminal><CNS Nervous System><CaM KII><CaM PK II><CaM kinase II><CaMKII><Causality><Cell Communication and Signaling><Cell Signaling><Central Nervous System><Chemosensitization><Chemosensitization/Potentiation><Chronic><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Communication><Complex><DLG4><DLG4 gene><Data><Defect><Development><Disease><Disorder><Disturbance in cognition><Drosophila><Drosophila genus><Dysfunction><E3 Ligase><E3 Ubiquitin Ligase><Early Infantile Autism><Electrophysiology><Electrophysiology (science)><Endowment><Ensure><Epilepsy><Epileptic Seizures><Epileptics><Escalante syndrome><Etiology><Fragile X><Fragile X Syndrome><Functional Imaging><Functional disorder><GeneHomolog><Generalized Growth><Genes><Genetic><Genetic Screening><Glutamate Receptor><Glutamates><Goals><Growth><Health><Homolog><Homologous Gene><Homologue><Human><Image><Impaired cognition><Infantile Autism><Intracellular Communication and Signaling><Invertebrata><Invertebrates><Kanner's Syndrome><L-Glutamate><Learning><Martin-Bell Syndrome><Martin-Bell-Renpenning syndrome><Mediating><Model System><Modeling><Modern Man><Molecular><Molecular Genetics><Motor Cell><Motor Neurons><Myoneural Junction><Nature><Nerve Degeneration><Nerve Impulse Transmission><Nerve Transmission><Nervous System><Nervous System Diseases><Nervous System Disorder><Neuraxis><Neurohumor Receptors><Neurologic Body System><Neurologic Disorders><Neurologic Organ System><Neurological Disorders><Neuromediator Receptors><Neuromuscular Junction><Neuron Degeneration><Neuronal Transmission><Neurophysiology / Electrophysiology><Neuroregulator Receptors><Neurotransmitter Receptor><Organism><PSD95><Pathway interactions><Peripheral Nervous System><Physiologic Imaging><Physiopathology><Potentiation><Primary Senile Degenerative Dementia><Process><Renpenning syndrome 2><Rodent><Rodentia><Rodents Mammals><Role><SAP90><Schizophrenia><Schizophrenic Disorders><Seizure Disorder><Seizures><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Synapses><Synaptic><Synaptic plasticity><System><Tail><Testing><Tissue Growth><Transmission><Ubiquitin Ligase Component Gene><Ubiquitin Ligase Gene><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Work><X-linked mental deficiency-megalotestes syndrome><X-linked mental retardation with fragile X syndrome><X-linked mental retardation-fragile site 1 syndrome><aminoacid><autism spectral disorder><autism spectrum disorder><autism-fragile X (AFRAX) syndrome><autistic spectrum disorder><axon signaling><axon-glial signaling><axonal signaling><biological signal transduction><calcium-dependent CaM kinase II><calmodulin-dependent protein kinase II><causation><cognitive dysfunction><cognitive loss><dementia praecox><density><developmental><disease causation><electrophysiological><epilepsia><epileptogenic><excitotoxic><excitotoxicity><experience><experiment><experimental research><experimental study><experiments><flexibility><flexible><fra(X) syndrome><fra(X)(28) syndrome><fra(X)(q27) syndrome><fra(X)(q27-28) syndrome><fragile X-mental retardation syndrome><fragile Xq syndrome><fragile site mental retardation 1><fruit fly><gene interaction><glia signaling><glial signaling><glutamatergic><imaging><imaging approach><imaging based approach><innovate><innovation><innovative><insight><living system><macro-orchidism-marker X (MOMX) syndrome><macro-orchidism-marker X syndrome><mar(X) syndrome><marker X syndrome><mental retardation-macroorchidism syndrome><motoneuron><nerve signaling><neural control><neural degeneration><neural regulation><neural signaling><neurodegeneration><neurodegenerative><neurological degeneration><neurological disease><neuromodulation><neuromodulatory><neuronal degeneration><neuronal signaling><neuropsychiatric disease><neuropsychiatric disorder><neuroregulation><neurotransmission><neurotransmitter release><novel><ontogeny><pathophysiology><pathway><pharmacologic><physiological imaging><postsynaptic><presynaptic><primary degenerative dementia><receptor function><recruit><scaffold><scaffolding><schizophrenic><senile dementia of the Alzheimer type><sleep behavior><sleep habit><social role><super high resolution><superresolution><synapse><synapse function><synaptic function><transmission process><ubiquitin ligase><ubiquitin-protein ligase><ultra high resolution>