Electrical role of dendritic spines

树突棘的电作用

• 批准号: 9020278
• 负责人: DEJAN P ZECEVIC
• 金额: $ 38.39万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9020278
• 关键词: AMPA Receptors; Autistic Disorder; Behavior; Behavior Therapy; Biological; Brain; Caliber; Complex; Computer Simulation; Data; Dendrites; Dendritic Spines; Deterioration; Development; Down Syndrome; Electrical Resistance; Electrodes; Elements; Epilepsy; Event; Excitatory Postsynaptic Potentials; Glutamates; Goals; Gold; Head; Health; Image; Individual; Kinetics; Learning; Location; Measurement; Measures; Mediating; Memory; Mental disorders; Methodology; Methods; Mind; Modeling; Monitor; N-Methyl-D-Aspartate Receptors; Neck; Neurons; Optics; Pathology; Physiology; Process; Property; Receptor Activation; Reporting; Research; Resistance; Resolution; Role; Schizophrenia; Shapes; Signal Transduction; Site; Slice; Structure; Surface; Synapses; Synaptic Potentials; Synaptic Transmission; Synaptic plasticity; Testing; Vertebral column; base; biophysical properties; clinically relevant; cognitive function; desensitization; driving force; effective therapy; electric impedance; electrical property; functional status; information processing; insight; meetings; nervous system disorder; neurophysiology; neuropsychiatric disorder; novel; novel strategies; postsynaptic; receptor; sound; tool; voltage; voltage gated channel

 DESCRIPTION (provided by applicant): Dendritic spines are small protrusions that mediate most of the excitatory synaptic transmission in the brain. Their electrical structure and function have long been recognized as essential for understanding how circuits of interconnected neurons encode information and mediate all aspects of behavior. Additionally, numerous reports of spine pathology in neurological and neuropsychiatric disorders including Down syndrome, autism, epilepsy, and schizophrenia highlight their clinical relevance. In spite of their clear biological importance, a complete and consistent description of the electrical structure and function of dendritic spines is not available. To meet this challenge, a novel method of high-sensitivity optical recording was developed to monitor integration of electrical events from individual dendritic spines, miniscule structures less than 1 micrometer in diameter. These measurements, which have never been possible before, pave the way to a new line of research in synaptic physiology of spines. The patch electrode is the gold standard in neurophysiology but is limited in two fundamental ways. First, it only allows measurement near the point of attachment. Second, we cannot attach pipettes to small surfaces, such as spine heads. A novel approach to voltage-imaging solves both these problems. At the conceptual level, a fundamental question that has not been answered is whether the electrical isolation of spine heads by a narrow spine neck provides specific functions which are not available to synapses on dendrites. Several such functions have been postulated, based on modeling and indirect evidence, although they have not been directly or definitively demonstrated: (1) Spines standardize and enhance synaptic activation of voltage-sensitive channels. (2) Changes in the electrical resistance of the spine neck under activity control mediate synaptic plasticity underlying learning and memory formation. (3) Electrical properties of spines promote nonlinear dendritic integration and associated forms of plasticity, thus fundamentally enhancing the computational capabilities of neurons. (4) Spines have the capacity to act as a discrete electrogenic compartments that amplify synaptic potentials by activation of voltage-sensitive channels. It is critical to test these postulates experimentally. If verified, these spine function would define their electrical role and, thus, would represent a potential substrate for pathologica changes and treatments. A novel optical recording will be used in brain slices combined with patch electrode recordings, glutamate uncaging, and computational models to evaluate the above hypotheses by direct recordings of electrical signaling in spines. These measurements will provide fundamental insight about the electrical structure of dendritic spines which is vital or understanding both physiology and pathology of neuronal function.

 描述（由申请人提供）：树突棘是介导大脑中大部分兴奋性突触传递的小突起。它们的电结构和功能长期以来被认为是理解相互连接的神经元回路如何编码信息和介导行为的各个方面的关键。此外，许多神经和神经精神疾病（包括唐氏综合征、自闭症、癫痫和精神分裂症）的脊柱病理学报告突出了其临床相关性。尽管树突棘具有明确的生物学重要性，但对树突棘的电结构和功能还没有完整和一致的描述。为了应对这一挑战，开发了一种高灵敏度光学记录的新方法，以监测来自单个树突棘的电事件的集成，树突棘是直径小于1微米的微小结构。这些以前从未有过的测量为脊柱突触生理学的新研究路线铺平了道路。贴片电极是神经生理学的金标准，但在两个基本方面受到限制。首先，它只允许在附着点附近进行测量。其次，我们不能将移液器连接到小表面，例如脊柱头。一种新的电压成像方法解决了这两个问题。在概念层面上，一个尚未得到回答的基本问题是，狭窄的脊柱颈部是否提供了特定的功能，而这些功能是树突上的突触所不具备的。基于建模和间接证据，已经假设了几个这样的功能，尽管它们还没有被直接或明确地证明：（1）棘标准化和增强电压敏感通道的突触激活。(2)在活动控制下，脊椎颈电阻的变化介导了学习和记忆形成的突触可塑性。(3)棘的电特性促进非线性树突整合和相关形式的可塑性，从而从根本上提高神经元的计算能力。(4)棘有能力作为一个离散的产电室，通过激活电压敏感通道放大突触电位。关键是要用实验来检验这些假设。如果得到证实，这些脊柱功能将确定其电作用，因此，将代表病理变化和治疗的潜在基质。一种新的光学记录将被用于脑切片结合贴片电极记录，谷氨酸释放，和计算模型，以评估上述假设的直接记录的电信号在脊柱。这些测量将提供有关树突棘的电结构的基本见解，这是至关重要的或理解神经元功能的生理学和病理学。