Synaptic Transmission During Neuronal Differentiation

描述（由申请人提供）：单侧外周前庭病变导致眼球运动、姿势和平衡缺陷，但由于前庭代偿过程，静态症状通常迅速减轻。前庭核神经元必须是完整的恢复，这表明适应涉及这些神经元。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。我们广泛的长期目标是确定病变后早期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然未得到补偿，因此研究了对照、补偿和未补偿的受试者。实验集中在一个不同的类前庭核神经元，切向核的主要细胞，从一个既定的动物模型，鸡。像人类一样，大多数鸡对单侧前庭神经节切除术的反应是迅速补偿，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，三天，大多数动物都有补偿。我们假设，在完整的初级前庭输入和/或非前庭输入的变化占主导地位的每个阶段的恢复。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，以及前庭神经和非前庭神经刺激的突触后反应。我们将确定记录的PC中电压依赖性钠通道和AMPA受体亚基表达的位置和密度。切向核中非前庭终末的确切性质将使用生物胞素细胞外注射，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来确定。病变在脊髓损害的生活质量和生存的病人。在前庭综合征发作后立即使用药物干预可以极大地改善患者的康复。随着我们更多地了解前庭神经核神经元水平上前庭传入阻滞引起的病理学，可以选择性地靶向有效的治疗，以改善平衡障碍患者的临床管理。

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.