Presynaptic receptors and analog signaling in the CNS

中枢神经系统中的突触前受体和模拟信号传导

• 批准号: 8484455
• 负责人: CRAIG E JAHR
• 金额: $ 32.51万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484455
• 关键词: Action Potentials; Affect; Age; Axon; Biochemical; Brain; Calcium; Calcium Channel; Cells; Consensus; Dendrites; Dependence; Dimensions; Disease; Distal; Distant; Electrophysiology (science); Fire - disasters; Frequencies; Glutamates; Image; Interneurons; Knowledge; Laser Scanning Microscopy; Lasers; Location; Long-Term Depression; Membrane; Membrane Potentials; Modeling; Molecular Structure; N-Methyl-D-Aspartate Receptors; Nature; Neurologic; Neurons; Physiological; Physiology; Presynaptic Receptors; Probability; Process; Property; Pyramidal Cells; Receptor Activation; Recording of previous events; Regulation; Relative (related person); Reporting; Signal Transduction; Site; Structure of molecular layer of cerebellar cortex; Synapses; Techniques; Testing; Varicosity; Visual Cortex; analog; barrel cortex; cell type; density; dentate gyrus; digital; experience; gamma-Aminobutyric Acid; granule cell; hippocampal pyramidal neuron; information processing; interest; mossy fiber; neuronal cell body; presynaptic; receptor; receptor expression; synaptic function; therapy design; two-photon; voltage

DESCRIPTION (provided by applicant): The likelihood of transmitter release from presynaptic release sites is regulated by several factors including the frequency of action potentials and the activity of presynaptic receptors. In addition to these mechanisms, subthreshold depolarizations of the somatodendritic compartment recently have been shown to alter action potential-driven release at distant locations of the axon. This form of regulation of release is analog in nature, i.e., though it alters the probability of release to an action potential, its potential to alter reease requires neither action potentials nor local receptor activation. Rather, these subthreshold depolarizations passive spread through the axon and are reported to affect release by calcium-dependent and calcium-independent mechanisms. Analog signaling adds another dimension to the control of neuronal circuit function which depends not only on the history of action potential frequency but also on the subthreshold changes in membrane potential that preceded a given action potential. Presynaptic receptors can also regulate release probability and alter the axonal membrane potential. The changes in axonal membrane potential can passively propagate antidromically and alter the excitability of the axon initial segment, a function which until recently was thought to be the exclusive domain of synapses on the somatodendritic membrane. The objective of this proposal is to determine the mechanisms underlying orthodromic and antidromic analog signaling and to determine if these mechanisms are used generally in the CNS. Orthodromic signaling will be studied in three dissimilar neurons, cerebellar molecular layer interneurons, dentate gyrus granule cells and cortical layer 5 pyramidal cells. The proposed mechanisms for orthodromic signaling in these three cells types are contradictory but include both calcium-dependent and calcium-independent processes. Antidromic signaling has only been demonstrated in one neuronal type, cerebellar granule cells. Though a number of axonal receptor types may affect initial segment excitability, NMDA receptors are particularly interesting candidates because of their use-dependence. Abundant evidence indicates that cortical layer 4 spiny stellate neurons in both visual and barrel cortex express presynaptic NMDA receptors that alter release properties and are required for the induction of long term depression. We will use two photon laser scanning microscopy, two photon laser uncaging and electrophysiology to determine the mechanisms of orthodromic analog signaling and the extent of presynaptic NMDA receptor expression, the physiological conditions necessary for their activation and their effects on the excitability of the axon initial segments of the layer 4 spiny stellate neurons.

描述（由申请人提供）：从突触前释放位点释放发射器的可能性受几种因素调节，包括作用频率和突触前受体的活性。除了这些机制外，最近已证明了躯体隔室的亚阈值去极化，可以改变轴突遥远位置的动作电位驱动释放。这种释放的调节形式本质上是类似物，即尽管它改变了释放的可能性，但其改变恢复的潜力既不需要动作电位，也不需要局部受体激活。相反，这些亚阈值去极化通过轴突被动扩散，据报道会影响钙依赖性和与钙独立的机制的释放。模拟信号传导为神经元电路函数的控制增加了另一个维度，这不仅取决于动作电位史的史，而且还取决于在给定动作电位之前的膜电位的下阈值变化。 突触前受体还可以调节释放概率并改变轴突膜电位。轴突膜电势的变化可以被动地传播抗胶粒并改变轴突初始段的兴奋性，直到最近，该函数被认为是Somatendendritic膜上突触的独家域。 该提案的目的是确定正质和抗胶粒模拟信号的基础机制，并确定CNS中是否通常使用这些机制。将在三个不同的神经元，小脑分子层中间神经元，齿状回颗粒细胞和皮质层5锥体细胞中研究正质信号传导。这三种细胞类型中正质信号传导的提议的机制是矛盾的，但包括钙依赖性和与钙无关的过程。 仅在一种神经元类型的小脑颗粒细胞中证明了抗肿瘤信号传导。尽管许多轴突受体类型可能会影响初始片段的兴奋性，但由于其使用依赖性，NMDA受体特别有趣。大量证据表明，在视觉和枪管皮层中的皮质层4丝状神经元都表示改变释放性能，这是诱导长期抑郁症所必需的。我们将使用两个光子激光扫描显微镜，两个光子激光渗透和电生理学来确定正常粒细胞模拟信号的机制以及突触前NMDA受体表达的程度，生理条件，其激活及其对轴突初始初始兴奋性所必需的生理条件 第4层刺晶状神经元的片段。