Neurotransmission at the vestibular calyx synapse

前庭萼突触的神经传递

• 批准号: 7596253
• 负责人: Katherine Janet Rennie
• 金额: $ 25.69万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596253
• 关键词: AMPA Receptors; Action Potentials; Address; Adult; Axon; Cells; Characteristics; Chemicals; Code; Computer Simulation; Crista ampullaris; Data; Disease; Dizziness; Environment; Equilibrium; Esthesia; Experimental Models; Fiber; Frequencies; Gated Ion Channel; Genetic Programming; Gerbils; Glutamate Receptor; Glutamates; Goals; Hair; Hair Cells; Hodgkin Disease; Injection of therapeutic agent; Ion Channel; Kinetics; Ligands; Measures; Mediating; Medical; Membrane; Modeling; Movement; Neurons; Organ; Patch-Clamp Techniques; Pattern; Perfusion; Pharmacological Treatment; Physiological; Potassium Channel; Preparation; Process; Property; Rennie; Reporting; Research Personnel; Resistance; Rodent; Role; Sensory; Shapes; Signal Transduction; Simulate; Stereocilium; Stimulus; Synapses; Synaptic Transmission; System; Techniques; Testing; Turtles; Type I Hair Cell; Type II Hair Cell; Utricle structure; Variant; base; computerized data processing; electrical property; extracellular; mathematical model; nerve supply; neurotransmission; neurotransmitter release; novel; patch clamp; postnatal; postsynaptic; programs; quantum; receptor; receptor coupling; relating to nervous system; response; simulation; transmission process; voltage; voltage clamp

DESCRIPTION (provided by applicant): The goal of this proposal is to understand synaptic transmission at the vestibular type I hair cell/calyx synapse. Three classes of morphological afferents have been described in the amniote crista and utricle. Calyx units contact type I hair cells (HCI) exclusively, bouton units contact type II hair cells only & dimorphic units receive innervation from both bouton & calyx fibers (Goldberg, 2000). The physiological response dynamics of these three classes of fibers vary, with calyx units having the most irregular firing pattern & the lowest gains to rotational stimuli (Baird et al. 1988; Lysakowski et al. 1995). The reasons for these variations are unclear, but are hypothesized to include differences in hair cell mechano-electrical transduction (MET) properties & differences in the biophysical membrane properties of primary vestibular afferents. We will study HCI & associated calyx afferents to determine how firing patterns in this unique terminal are shaped by both pre- & post-synaptic mechanisms. In Aim 1, patch clamp techniques will be used to study ionic conductances & transmitter release in a newly developed preparation of calyx terminals isolated together with HCI from gerbil vestibular organs (Rennie & Streeter, 2006). Excitatory postsynaptic currents (EPSCs) resulting from hair cell transmitter release will be recorded from calyx terminals under a variety of conditions. In Aim 2 we will record MET currents & receptor potentials from HCI during displacement of the hair bundle with a stiff probe in a wholemount utricle preparation. In Aim 3, mathematical modeling techniques will be employed to simulate HCI & calyx responses to glutamate. The passive electrical properties of the calyx & attached axon will be simulated with a segmented computational model in the NEURON programming environment. Na+, Ca2+ and K+ channels will be modeled with Hodgkin-Huxley style rate constants using the experimental data obtained in Aims 1& 2. A genetic algorithm wiil be used to optimize the kinetic parameters for the activation & inactivation of ionic conductances. Dizziness is one of the most common medical complaints. Understanding the basic cellular mechanisms of balance sensation is essential to lay the groundwork for identifying causes & cures for this debilitating condition. The combination of experimental & modeling approaches will elucidate how sensory information is transformed by HC1 & converted into a neural code by their afferents.

描述（由申请人提供）：本提案的目标是了解前庭 I 型毛细胞/萼突触的突触传递。羊膜嵴和椭圆囊中描述了三类形态传入神经。花萼单位专门接触 I 型毛细胞 (HCI)，布顿单位仅接触 II 型毛细胞，二态性单位接受布顿和花萼纤维的神经支配 (Goldberg, 2000)。这三类纤维的生理反应动力学各不相同，花萼单元具有最不规则的放电模式和最低的旋转刺激增益（Baird 等人，1988 年；Lysakowski 等人，1995 年）。这些差异的原因尚不清楚，但推测包括毛细胞机电转导 (MET) 特性的差异和初级前庭传入生物物理膜特性的差异。我们将研究 HCI 和相关的花萼传入神经，以确定突触前和突触后机制如何塑造这个独特终端的放电模式。在目标 1 中，膜片钳技术将用于研究新开发的与沙鼠前庭器官 HCI 一起分离的萼末端制剂中的离子电导和递质释放（Rennie 和 Streeter，2006）。毛细胞递质释放产生的兴奋性突触后电流 (EPSC) 将在各种条件下从花萼末端记录下来。在目标 2 中，我们将在整体椭圆囊制剂中用刚性探针记录发束移位期间来自 HCI 的 MET 电流和受体电位。在目标 3 中，将采用数学建模技术来模拟 HCI 和花萼对谷氨酸的反应。花萼和附着轴突的被动电特性将在 NEURON 编程环境中使用分段计算模型进行模拟。 Na+、Ca2+ 和 K+ 通道将使用目标 1 和 2 中获得的实验数据，通过 Hodgkin-Huxley 式速率常数进行建模。遗传算法将用于优化离子电导激活和失活的动力学参数。头晕是最常见的医疗病症之一。了解平衡感的基本细胞机制对于确定这种令人衰弱的疾病的原因和治疗方法奠定基础至关重要。实验和建模方法的结合将阐明 HC1 如何转换感觉信息并通过传入神经将其转换为神经代码。