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Modulation of calcium-mediated plasticity signals in dendritic spines

树突棘中钙介导的可塑性信号的调节

基本信息

批准号：
10228584
负责人：
Andrew Landau
金额：
$ 2.73万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2022-05-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228584
关键词：
Accounting Action Potentials Address Affect Area Binding Brain Buffers Calcium Calcium Channel Calcium Signaling Calcium ion Chemosensitization Cytoplasm Data Dendritic Spines Detection Disease Electrophysiology (science)Excitatory Postsynaptic Potentials Exhibits Functional disorder Generations Glutamate Receptor Glutamates Human Human Pathology Individual Intellectual functioning disability Investigation Kinetics L-Type Calcium Channels Laboratory Animals Lead Learning Maps Measurement Measures Mediating Mental Depression Methodology Methods Modeling Movement Mutation N-Methylaspartate Neurodegenerative Disorders Neurons Neurophysiology - biologic function Pattern Physiological Protocols documentation Pyramidal Cells Research Resolution Shapes Signal Transduction Slice Synapses Synaptic Transmission Synaptic plasticity Time Vertebral column autism spectrum disorder biophysical model calcium indicator cell type classical conditioning experimental study gamma-Aminobutyric Acid innovation nervous system disorder neuropathology new technology postsynaptic prevent receptor binding relating to nervous system response signal processing synaptic function therapy development two photon microscopy

项目摘要

Synaptic transmission is regulated by calcium-dependent plasticity signals in the brain. Most calcium signals arise from voltage-dependent calcium channels which are activated by neural activity. Extensive research has identified how particular patterns of activity drive plasticity. For example, in the case of spike-timing dependent plasticity, the timing between glutamatergic input and postsynaptic APs determines the sign and magnitude of plasticity. Although calcium signals evoked by activity are necessary for the generation of plasticity, the mapping between calcium signals and specific plasticity responses is still unclear. In this proposal, we hypothesize that accounting for distortions in measurements of calcium signals imposed by the use of fluorescent calcium indicators will elucidate how calcium signals activate synaptic plasticity. To address this hypothesis, we have established a method of measuring calcium currents, which are independent of the distortion imposed by fluorescent calcium indicators. In Aim 1, we will develop a complete model of synaptic calcium handling to enable measurements of physiological calcium signals. In Aim 2, we will apply these methods to understand how coincident activation of glutamatergic input and postsynaptic action potentials drives calcium signals and whether it can explain the time course of spike-timing dependent plasticity. Inhibition can spatially restrict and prevent plasticity from occurring. This function is important for associative learning and is disrupted in human neurological diseases. However, methodological challenges have prevented investigations of the mechanisms of inhibitory control of plasticity. In Aim 3, we will combine our method of measuring calcium currents with two new technologies that enable extremely detailed investigations of inhibitory control of synaptic calcium signals. We will measure how inhibition modulates synaptic calcium signals and determine the effect of this modulation on the induction of plasticity. In summary, this proposal provides an important methodological innovation that will significantly progress our understanding of fundamental neural functions. The results of these investigations will provide a framework for understanding how synaptic plasticity is regulated and may guide the development of therapies for neurogenerative disease.

突触传递受脑内钙依赖性可塑性信号的调控。大多数钙信号