The role of short-term plasticity at the calyx of Held for auditory processing

描述（由申请人提供）：听觉脑干或皮层中的突触传递缺陷可引起中枢听觉处理障碍，其中大脑不能正确处理声音。研究听觉脑干中控制听觉过程的突触机制将有助于更好地理解人类听力障碍的病因。拟议的研究的长期目标是确定在听觉脑干突触（称为Held的萼）管理短期可塑性的机制，并确定该突触可塑性对声音定位的功能重要性。Held萼是听觉脑干中的一个巨大的神经元能突触，其功能是作为声音定位的快速兴奋性突触。花萼表现出一种称为强直后增强（PTP）的短期可塑性，它可以由高频（强直）刺激诱导，并依赖于突触前残留Ca 2+浓度的升高。具体而言，突触前Ca 2+的增加激活蛋白激酶C（PKCCa）的Ca 2+依赖性亚型。虽然长期以来，人们一直将花萼作为突触模型进行研究，但尚未探讨PTP在花萼的生理意义。萼是投射到斜方体内侧核（MNTB）的主要神经元上的谷氨酸突触。MNTB？最近发现LSO突触在听力发作前的突触细化期间共同释放谷氨酸/GABA/甘氨酸。假设肾盏PTP调制的保真度和时间精度的MNTB射击仍然未知，并增加释放概率在MNTB？LSO突触有利于突触传递。因此，像PTP这样的短期可塑性形式可能在塑造声音定位脑干回路中发挥重要作用。本研究计划的具体目的是（1）确定在生理条件下Held萼PTP的动力学，（2）研究脑干声音定位通路中萼PTP的功能作用，（3）解剖PTP分子级联，以选择性地改变萼的短期可塑性。用于实现这些目标的主要技术包括全细胞电生理学记录、脑切片中的大量突触前Ca 2+加载和Ca 2+瞬变的双光子成像。该提案的完成将使人们对和平与贸易方案在一个 听觉脑干的关键突触Wade Regehr博士的专业知识和哈佛医学院的环境为我提供了完成目标所必需的电生理学和成像技术方面的广泛培训。

DESCRIPTION (provided by applicant): Defects in synaptic transmission in the auditory brainstem or cortex can give rise to central auditory processing disorders where the brain cannot correctly process sound. Investigating the synaptic mechanisms governing the processes of hearing in the auditory brainstem will allow for a better understanding of the etiology of human hearing disorders. The long-term objectives of the proposed research are to define the mechanisms that govern short-term plasticity at the auditory brainstem synapse called the calyx of Held, and to determine the functional importance of plasticity at this synapse for sound localization. The calyx of Held is a giant glutamatergic synapse in the auditory brainstem that functions as a fast excitatory synapse for sound localization. The calyx displays a form of short-term plasticity called post-tetanic potentiation (PTP), which can be induced by high-frequency (tetanic) stimulation and is dependent on elevations in presynaptic residual Ca2+ concentrations. Specifically, increases in presynaptic Ca2+ activate Ca2+-dependent isoforms of protein kinase C (PKCCa). While the calyx has long been studied as a model synapse, the physiological significance of PTP at the calyx has not been explored. Calyces are glutamatgeric synapses that project onto principal neurons of the medial nucleus of the trapezoid body (MNTB). The MNTB ?LSO synapse has been recently discovered to co-release glutamate/GABA/glycine during the period of synaptic refinement prior to hearing onset. Calyceal PTP is hypothesized to modulate the fidelity and temporal precision of MNTB firing remains unknown, and to increase release probability at the MNTB?LSO synapse to favor glutamatergic transmission. Thus, forms of short-term plasticity like PTP could play a major role in shaping the sound localization brainstem circuit. The specific aims of this research proposal are to (1) determine the dynamics of PTP under physiological conditions at the calyx of Held, (2) investigate the functional role of calyceal PTP in the brainstem sound localization pathway, and (3) dissect the PTP molecular cascade to selectively alter short-term plasticity at the calyx. The primary techniques used to achieve these aims include whole-cell electrophysiology recordings, bulk presynaptic Ca2+ loading in brain slices, and two-photon imaging of Ca2+ transients. The completion of this proposal will provide considerable insight into the functional roles of PTP at a key synapse in the auditory brainstem. The expertise of Dr. Wade Regehr and the environment of Harvard Medical School provide me with extensive training in electrophysiology and imaging techniques necessary to complete my goals.