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Administrative Supplement (Diversity) to Generating functional diversity from molecular homogeneity at glutamatergic synapses

从谷氨酸能突触的分子同质性生成功能多样性的行政补充（多样性）

基本信息

批准号：
10841899
负责人：
DION KAI DICKMAN
金额：
$ 3.36万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10841899
关键词：
Action Potentials Address Administrative Supplement Alzheimer&apos s Disease Biological Models Botulinum Toxins Calcium Calibration Chemosensitization Clustered Regularly Interspaced Short Palindromic Repeats Communication Coupling Data Defect Development Disease Drosophila genus Electrophysiology (science)Epilepsy Etiology Failure Genes Genetic Glutamates Goals Health Heterogeneity Homologous Gene Individual Mammals Mental disorders Microscopy Modeling Molecular Molecular Machines Motor Motor Neurons Muscle Muscle Contraction Mutagenesis Nanostructures Nervous System Neurodegenerative Disorders Neurodevelopmental Disorder Neuromuscular Junction Neurons Neurophysiology - biologic function Orthologous Gene Phase Positioning Attribute Process Property Protein Isoforms RNA Splicing Reagent Reporter Role Schizophrenia Site Structure Synapses Synaptic plasticity System Toxic effect Vesicle autism spectrum disorder botulinum toxin type C experience experimental study fly imaging approach innovation insight nanoscale nervous system disorder neural circuit neuropsychiatric disorder neurotransmission neurotransmitter release postsynaptic presynaptic prevent ratiometric scaffold superresolution imaging synaptic function transmission process ultra high resolution

项目摘要

PROJECT SUMMARY Synapses are fundamental units of communication in the nervous system, where immense diversity in structure and function serve to tune and calibrate information transfer. Defects in the ability of synapses to properly diversify contribute to the etiology of a variety of neurodevelopmental, psychiatric, and neurodegenerative diseases. One means of generating diversity in synaptic function is through molecular heterogeneity, where combinations of distinct genes are expressed at individual synapses to enable specific functional properties. However, it has become increasingly clear, though difficult to resolve, that remarkable synaptic diversity can be achieved from a limited set of molecular machinery. In principle, the Drosophila neuromuscular junction (NMJ) is a uniquely powerful model to address how synaptic diversity is generated given the sophisticated genetic, electrophysiological, and imaging approaches. In this system, two distinct motor neurons converge to co-innervate individual muscle targets, where transmission from a strong and weak input together drive muscle contraction in the motor circuit. However, an inability to selectively isolate transmission from either input has been a major limitation towards understanding synaptic diversity in this system. Here, we propose to use expression of a unique Botulinum NeuroToxin (BoNT) to selectively silence transmission at strong or weak synaptic inputs. Preliminary data suggests that while each neuron is largely composed of the same molecular machinery at active zones, one core component, previously thought to function universally at all active zones, actually subserves dramatically different roles at strong vs weak synapses. We will use BoNT silencing, super resolution imaging, and the latest calcium reporters targeted to release sites to illuminate differences in active zone nanostructure and function between strong and weak synapses. We will also leverage new innovations in CRISPR mutagenesis to dissect the specialized functions of eight core active zone components at strong vs weak synapses. Finally, we will interrogate how these core active zone components are uniquely targeted for modulation and remodeling at strong vs weak synapses in the context of homeostatic synaptic plasticity. Together, these approaches will unlock fundamental insights into how glutamatergic synaptic diversity is established and adaptively modified through plasticity. Ultimately, this understanding will illuminate key mechanisms through which heterogeneous functional properties at glutamatergic release sites are enabled by a limited molecular toolkit.

项目总结