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Trans-synaptic control of presynaptic neurotransmitter release

突触前神经递质释放的跨突触控制

基本信息

批准号：
9284531
负责人：
EDWARD L STUENKEL
金额：
$ 43.16万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9284531
关键词：
Address Anatomy Autistic Disorder Behavior Control Binding Biochemical Biological Assay Biological Neural Networks Brain Brain-Derived Neurotrophic Factor Central Nervous System Diseases Code Communication Complex Data Development Disease Elements Epilepsy Equilibrium Evaluation Exhibits FRAP1 gene Family GTP Binding Genetic Models Glutamates Goals Guanosine Triphosphate Phosphohydrolases Health Hereditary Disease Hippocampus (Brain)Human Hyperactive behavior Individual Intellectual functioning disability Investigation Lead Learning Link Location Maintenance Maps Mediating Memory Modification Molecular Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Pathway interactions Play Probability Process Protein Biosynthesis Proteins Receptor Signaling Recycling Regulation Reproducibility Rest Role SNAP receptor Seizures Signal Pathway Signal Transduction Signaling Protein Site Slice Synapses Synaptic plasticity System Testing Translation Initiation Ubiquitin Ubiquitination Vesicle Work autism spectrum disorder in vivo insight mossy fiber multicatalytic endopeptidase complex mutant nervous system disorder neural circuit neuronal excitability neuropsychiatric disorder neurotransmitter release novel optical imaging optogenetics postsynaptic presynaptic response synaptic function translation factor ubiquitin-protein ligase

项目摘要

Abstract: A severe health burden imposed by many neuropsychiatric and neurological diseases can be linked to limitations in, or disruption of, molecular pathways which guide development, maintenance or plasticity of synaptic connections. Importantly, as many neural circuits are persistently active the individual synaptic connections must undergo continuous and coordinated homeostatic changes to counteract continual synaptic strengthening/weakening and development of network instability. Thus, developing a functional map of sites of activity- dependent dynamic coordination of the molecules and signaling pathways that define the process is central to enabling an understanding of many CNS diseases. The work proposed is uniquely important as it will elucidate novel and yet potent molecular signaling pathways that mediate accurate and reproducible activity-dependent adaptations in synaptic efficacy. Specifically, investigations focus on understanding how post-synaptic sensing of activity via the mTORC1/BDNF signaling pathway mediates increased presynaptic neurotransmitter release during reduced excitatory input to the post-synaptic element. Investigations will test the hypothesis that tomosyn-1 is a central presynaptic target of mTORC1/BDNF/TrkB receptor signaling and that trans-synaptic adjustments in presynaptic neurotransmitter release via this signaling pathway occur via UPS regulation of tomosyn-1 protein levels. We will also define specific sites within the secretory pathway by which tomosyn exerts control over presynaptic neurotransmitter release. Commonality of this trans-synaptic mechanism will also involve comprehensive evaluation at Mossy fiber/CA3 and at CA3/CA1 synapses of hippocampal brain slices, as these circuits are known to exhibit strikingly divergent synaptic plasticity. In addition, we will characterize the E3 ligase responsible for UPS regulation of tomosyn, determine if the E3 ligase activity is sensitive to mTORC1/BDNF/TrkB signaling and if ubiqutination of tomosyn by the E3 ligase regulates tomosyn protein levels and neurotransmitter release. The investigations employ state of the art optical imaging of vesicle cycling, genetic models targeting protein/signaling function, optogenetic control of neuronal excitability and analysis of synaptic function in cultures of hippocampal neurons and hippocampal slices. Biochemical assays will quantify and establish activity dependent control on tomosyn protein via the UPS. This information will significantly advance understanding on mechanisms by which activity- dependent changes in post-synaptic mTORC1 activity coordinate spatial and temporal adjustments in presynaptic neurotransmitter release.

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