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Principal Investigator: Adam C Miller
Organization: UNIVERSITY OF OREGON
Fiscal Year: 2024
Award: $587,222
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
All of brain function, from sensory perception to behavior, is derived from the pattern and properties of the
synaptic connections among billions (in humans) of individual neurons. The long-term goal of this project is to
understand molecular pathways that regulate electrical synapse formation in vivo. Electrical synapses are sites
of direct communication between neurons, formed by gap junctions, that allow the passage of ions and small
molecules. They contribute extensively to neural circuit formation and function, both during development as
well in adulthood, acting in sensory perception, central processing, and motor output. Moreover, they are
thought to be disrupted in numerous human disorders, such as autism, epilepsy, and myopia. A major gap in
the field is that the molecular mechanisms controlling the formation of electrical synapses are poorly
understood. This proposal utilizes the zebrafish Mauthner circuit to investigate the genetics, cell biology, and
biochemistry of electrical synapse formation and function. Mauthner neurons are individually identifiable and
their pre- and postsynaptic partners, synapses, and function are exquisitely visualized in a living, vertebrate
embryo. Using the genetic accessibility of zebrafish, we have found that a family of membrane-associated
guanylate kinase scaffolds, the “ZO-family”, are required for gap junction channel localization and electrical
synapse function. These findings suggest that electrical synapses are comprised of an emerging molecular
complexity, and our goal is to uncover the cellular and molecular functions of the ZO-family in building
functional neuronal gap junctions. Aim1 will determine how the ZO-family proteins direct the cell biological
construction of electrical synapses in vivo. Aim2 will identify the molecular interactions utilized by the ZO-family
proteins in directing electrical synapse formation in vivo. Aim3 will reveal the functional impacts of ZO-family
proteins on synaptic transmission and behavior. The proposed studies will provide novel insight into the
mechanisms of electrical synapse formation and provide a foundation for the identification of therapeutic
targets for complex neurodevelopmental disorders.
Terms: <21+ years old><ASD><Adopted><Adult><Adult Human><Autism><Autistic Disorder><Behavior><Behavioral><Binding><Biochemical><Biochemistry><Biologic Models><Biological><Biological Chemistry><Biological Function><Biological Models><Biological Process><Brachydanio rerio><Brain><Brain Nervous System><CNS Nervous System><Cell Adhesion><Cell Body><Cell Culture Techniques><Cell Transplantation><Cells><Cellular Adhesion><Cellular Matrix><Cellular biology><Central Nervous System><Chemical Synapse><Chemicals><Co-Immunoprecipitations><Communicating Junction><Communication><Complex><Cytoplasm><Cytoskeletal System><Cytoskeleton><Danio rerio><Defect><Development><Disease><Disorder><Early Infantile Autism><Electrical Synapse><Electrons><Electrophysiology><Electrophysiology (science)><Encephalon><Epilepsy><Epileptic Seizures><Epileptics><Family><Foundations><Gap Junctions><Genes><Genetic><Goals><Health><Human><Image><In vivo analysis><Individual><Infantile Autism><Injury><Ions><Kanner's Syndrome><Knowledge><Link><Liquid substance><Low-resistance Junction><MAGUK enzyme><Mauthner's neuron><Mediating><Medical><Microscopy><Model System><Modeling><Modern Man><Molecular><Molecular Interaction><Motor><Motor output><Myopia><Nearsightedness><Negative Beta Particle><Negatrons><Nerve Cells><Nerve Unit><Neural Cell><Neural Transmission><Neuraxis><Neurocyte><Neurodevelopmental Disorder><Neurological Development Disorder><Neurons><Neurophysiology / Electrophysiology><Nexus Junction><Occluding Junctions><Outcome><Pathway interactions><Pattern><Perception><Performance><Phase><Physiology><Property><Protein Family><Publishing><Role><Seizure Disorder><Sensory><Site><Specificity><Structure><Synapses><Synaptic><Synaptic Transmission><System><Tight Junctions><Transmission><Visualization><Work><Zebra Danio><Zebra Fish><Zebrafish><Zonula Occludens><adulthood><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><biologic><cell biology><cell culture><cell cultures><cellular transplant><density><developmental><electrophysiological><epilepsia><epileptogenic><fluid><gap junction channel><human disease><imaging><in vivo><in vivo evaluation><in vivo testing><injuries><innovate><innovation><innovative><insight><intracellular skeleton><liquid><liquid dynamics><membrane-associated guanylate kinase><mutant><near vision><neural><neural circuit><neural circuitry><neural network><neurocircuitry><neurodevelopmental disease><neurogenetics><neuronal><novel><pathway><postsynaptic><presynaptic><scaffold><scaffolding><small molecule><social role><synapse><synapse formation><synapse function><synaptic circuit><synaptic circuitry><synaptic function><synaptogenesis><therapeutic target><tool><trafficking><transmission process><vertebrate embryos>