Many neurological disorders are associated with an imbalance between excitatory and inhibitory (E/I) neuronal signaling. The nervous system normally maintains an E/I balance by regulating the number or strength of synaptic connections between neurons. Neurons in the human brain are outnumbered nearly ten to one by non-neuronal glial cells, which provide support for neuronal function. While maintaining the richness of neuronal signaling, the reduced cellular complexity of the roundworm, Caenorhabditis elegans (C. elegans), makes it an excellent model system to study E/I balance. The overall goal of this proposal is to elucidate how non-neuronal cells and neurons interact to regulate E/I balance. By understanding how glial cells and neurons interact, this project will provide novel insights into the treatment and management of neurological disorders such as epilepsy, autism spectrum, or schizophrenia. C. elegans will be used as a model for this project for the following reasons: 1) its nervous system has been fully mapped, 2) it's been widely used to study how neuronal networks are formed and maintained, 3) the genes and molecular mechanisms that regulate nervous system function are conserved with humans, and 4) it is easy to manipulate through genetic techniques. For these reasons, C. elegans provides a simple model to study the molecular mechanisms that underlie neurological disorders associated with E/I imbalance. The goals of this study will be accomplished through the following specific aims:
Aim 1 : Determine how the two immunoglobulin domain transmembrane protein, ZIG-10, regulates the phagocytosis pathway to balance excitatory and inhibitory neurotransmission using electron microscopy and electrophysiology.
Aim 2 : Elucidate the ZIG-10 signaling pathway in maintaining synaptic connections using genetic, cell biologic, and biochemical approaches.
Aim 3 : Determine how a novel transporter regulates neuronal activity and E/I balance in vivo. The completion of this proposal will provide a deeper understanding of how neurons and non-neuronal glia cooperate to regulate E/I balance. Additionally, this study will uncover the mechanism(s) affecting aberrant neuronal activity associated with neurological disorders. Finally, this project will identify potential therapeutic targets for novel treatments of autism spectrum disorders, epilepsy, schizophrenia, and related neurological diseases. The mentored portion of this award will take place at the University of California San Diego under the mentorship of Dr. Yishi Jin. UCSD and the superb neuroscience faculty provide an excellent environment for the proposed research, which employs electron microscopy and electrophysiology under the guidance of Dr. Mark Ellisman and Dr. Darwin Berg, leaders in their respective fields. Dr. Jin, a world-renowned geneticist and neurobiologist, will provide both the resources and guidance to accomplish the research proposed during the mentored phase. Through hands-on training and formal meetings with Dr. Ellisman and Dr. Berg, I will learn how to use new techniques to dissect the structure-function relationship of the nervous system. This will allow me to understand how neurons and non-neuronal cells interact to regulate E/I balance in the short-term. During the independent phase, applying these new techniques with my expertise in molecular and cellular biology and biochemistry will allow me to decipher how the E/I balance is regulated during normal and disrupted during disease states. Overall the research and career development proposed during this award will enable me to uncover the mechanisms that regulate E/I balance that is disrupted in many neurological disorders including epilepsy, schizophrenia, and autism spectrum.

Public Health Relevance

Neurological disorders, such as autism spectrum, epilepsy, and schizophrenia, are associated with imbalances in neuronal activity within the brain. There are currently no cures or long-term therapies to assuage the symptoms. This project will uncover mechanisms that regulate how neuronal activity is balanced and will provide novel therapeutic targets for future treatments.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Transition Award (R00)
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Neurological Sciences Training Initial Review Group (NST)
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Leenders, Miriam
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University of Kentucky
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United States
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