Dynamics of calcium signals control neurotransmitter release in retinal ribbon synapses.

钙信号的动力学控制视网膜带突触中神经递质的释放。

基本信息

项目摘要

Project Abstract Dementias, including those associated with Alzheimer's disease (AD), are major neurodegenerative disorders that cause visual problems due to pathologic changes in the retina and optic nerve and higher cortical impairment. In AD these include changes in contrast sensitivity, visual acuities, and color vision. Despite the growing idea that the retina can be used in early diagnosis of AD, little is known about the underlying mechanism associated with AD histopathology markers and visual impairment. These mechanisms must be deciphered for the development of effective therapeutics for AD. Sensory synapses in the retina rely on the proper function of the synaptic ribbon, which is a specialized organelle anchored to the presynaptic active zone. Synaptic dysfunction (synaptopathy) is a critical common biological mechanism that links protein pathologies to AD symptoms. The long-term goal of our parent research program is to reveal the regulation of Ca2+ signaling in retinal ribbon synapses during development, normal adulthood, and disease states that affect the retina. While in the parent research program focuses on local Ca2+signaling and its interplay with the vesicle replenishment required for neurotransmitter release, the supplementary research program will apply this knowledge to AD. Our approach to both projects uses a confluence of state-of-the-art techniques, including fluorescence imaging, voltage-clamp electrophysiology, computational modeling, electron microscopy of individual physiologically identified cells, and pharmacological tools. We will use a novel and robust model for AD in adult zebrafish treated with okadaic acid (OKA) that exhibits the holistic representation of important AD hallmarks and replicates the memory deficiencies of AD. Our central hypothesis is that AD histopathology hallmarks that develop in the retina of OKA-treated zebrafish result in the onset and progression of dysfunction of the bipolar retinal ribbon synapse by altering synaptic vesicle mobility, mitochondrial function, and calcium dysregulation. Our hypothesis is supported by recent studies in which OKA treatment of zebrafish resulted in the formation of major histopathological hallmarks of AD, including amyloid beta (Aβ) protein fragments, neurofibrillary tangles (NFTs), hyperphosphorylated tau protein, and accumulation of senile plaques, leading to neurodegeneration, cognitive impairments, oxidative stress, neuroinflammation, glial cell activation, glutamate excitotoxicity, and mitochondrial dysfunction. In objective 1, we will determine the synaptic vesicle dynamics in retinal bipolar cells isolated from OKA-treated zebrafish, while in objective 2, we will reveal the synaptic mitochondrial dysfunction and calcium signaling at ribbon synapses in OKA-treated zebrafish. The results of this research program will allow us to determine whether defects in synaptic vesicle mobility, synaptic mitochondrial dynamics, and local Ca2+ homeostasis are a prelude to future development of AD. Data generated from this proposal will extends beyond our specific investigation of bipolar cells to define the role of synapse loss and dysfunction in AD.
项目摘要

项目成果

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Thirumalini Vaithianathan其他文献

Thirumalini Vaithianathan的其他文献

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{{ truncateString('Thirumalini Vaithianathan', 18)}}的其他基金

Dynamics of calcium signals control neurotransmitter release in retinal ribbon synapses
钙信号的动力学控制视网膜带突触中神经递质的释放
  • 批准号:
    10540733
  • 财政年份:
    2021
  • 资助金额:
    $ 27.99万
  • 项目类别:
Dynamics of calcium signals control neurotransmitter release in retinal ribbon synapses
钙信号的动力学控制视网膜带突触中神经递质的释放
  • 批准号:
    10320486
  • 财政年份:
    2021
  • 资助金额:
    $ 27.99万
  • 项目类别:
Dynamics of calcium signals control neurotransmitter release in retinal ribbon synapses
钙信号的动力学控制视网膜带突触中神经递质的释放
  • 批准号:
    10576110
  • 财政年份:
    2021
  • 资助金额:
    $ 27.99万
  • 项目类别:

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