Synaptic Transmission During Neuronal Differentiation

描述(申请人提供)：单侧前庭周围性病变导致眼球运动、姿势和平衡障碍，但由于前庭代偿过程，静态症状通常会迅速消失。前庭核神经元必须完整才能恢复，这表明适应涉及到这些神经元。事实上，双侧前庭核神经元自发放电的恢复是前庭代偿进行的关键步骤。我们广泛的、长期的目标是确定在损伤后的早期阶段协调前庭核神经元活动变化的关键细胞和分子事件。由于相当大比例的患者仍未得到补偿，因此对对照组、补偿对象和未补偿对象进行了研究。实验的重点是一类截然不同的前庭核神经元，即切向核的主要细胞，来自已建立的动物模型鸡。像人类一样，大多数鸡对单侧前庭神经节切除的反应是快速补偿，但其他鸡仍然没有补偿。我们将研究两个关键阶段：损伤后一天，所有动物都没有补偿，以及三天，大多数动物已经补偿。我们假设，在恢复的每个阶段，完整的初级前庭输入和/或非前庭输入的变化是主导的。具体目标包括全细胞膜片钳记录兴奋性和抑制性自发突触事件的频率和动力学，以及对前庭神经和非前庭神经刺激的突触后反应。我们将确定电压依赖性钠通道的位置和密度以及记录的PC中AMPA受体亚单位的表达。使用生物细胞素胞外注射，结合谷氨酸和GABA免疫标记，以及损伤后终末的钾通道免疫标记，将确定切向核中非前庭终末的确切性质。迷路病变影响患者的生活质量和生存。在前庭综合征发作后立即使用药物干预可以极大地促进患者的康复。随着我们在前庭核神经元水平上对前庭去传入引起的病理学有更多的了解，有效的治疗可以选择性地被靶向，以改善平衡障碍患者的临床处理。

DESCRIPTION (provided by applicant): Unilateral peripheral vestibular lesions result in deficits in eye movements, posture, and balance, but the static symptoms usually diminish rapidly due to the process of vestibular compensation. Vestibular nuclei neurons must be intact for recovery, suggesting that adaptation involves these neurons. In fact, recovery of spontaneous spike firing in vestibular nuclei neurons bilaterally is a critical step for vestibular compensation to proceed. Our broad, long-term goal is to identify key cellular and molecular events orchestrating changes in vestibular nuclei neuron activity at early stages after lesions. Since a significant proportion of patients remain uncompensated, controls, compensated, and uncompensated subjects are studied. Experiments are focused on a distinct class of vestibular nuclei neurons, the principal cells of the tangential nucleus, from an established animal model, the chicken. Like humans, most chickens respond to unilateral vestibular ganglionectomy by compensating rapidly, but others remain uncompensated. We will study two critical stages: one day after the lesion when all the animals are uncompensated, and three days, when the majority of animals have compensated. We hypothesize that changes in the intact primary vestibular inputs and/or non-vestibular inputs dominate each stage of recovery. The specific aims include whole-cell patch-clamp recordings of frequency and kinetics of excitatory and inhibitory spontaneous synaptic events, and postsynaptic responses on vestibular-nerve and non-vestibular-nerve stimulation. We will determine the location and density of voltage-dependent sodium channels and AMPA receptor subunit expression in recorded PCs. The exact nature of non-vestibular terminals in the tangential nucleus will be determined using biocytin extracellular injections, combined with glutamate and GABA immunolabeling, and potassium channel immunolabeling of the terminals after lesions. Lesions in the labyrinths impair the quality of life and survival of the patient. Using drug interventions immediately after the onset of the vestibular syndrome could vastly improve patient rehabilitation. As we learn more about the pathology induced by vestibular deafferentation at the level of vestibular nuclei neurons, effective therapies can be targeted selectively to improve the clinical management of patients with balance disorders.