Synaptic mechanisms in the auditory system

描述(由申请人提供)：突触抑制机制代表了我们对脑干中声音信号处理的理解中的一些最大差距。神经元的亚型，它们相互连接的对象，这些连接的有效性，以及抑制信号的大小和形状是如何控制的，所有这些都还不清楚。考虑到作为药物靶点的抑制与其他脑区疾病之间的关系，对抑制系统的深入了解似乎对治疗听觉障碍具有临床意义。在这项提案中，我们将果断地解决其中的每一个问题，重点关注普遍存在的抑制性神经递质甘氨酸。首先，我们将利用绿色荧光蛋白(GFP)在抑制细胞亚群中表达的小鼠品系的可用性来揭示常见亚型听觉神经元的功能和连接，这些亚型很少使用直接电生理手段进行研究。其次，我们将确定控制抑制状态持续时间的机制，并重点介绍突触间隙中递质清除的作用以及GABA/甘氨酸共传递在调节甘氨酸能衰退中的前景。最后，我们将确定甘氨酸是兴奋还是抑制突触后神经元的机制。

DESCRIPTION (provided by applicant): Synaptic mechanisms of inhibition represent some of the greatest gaps in our understanding of the processing of acoustic signals in the brainstem. The subtypes of neurons, with whom they interconnect, the efficacy of those connections, and how the size and shape of the inhibitory signals are controlled, all these remain unclear. Given the relation between inhibition as a target for drugs and disease in other brain regions it seems likely that a deep knowledge of inhibitory systems will be of clinical relevance for treating auditory disorders. In this proposal, we will address decisively each one of these points, focusing on the ubiquitous inhibitory neurotransmitter glycine. First, we will take advantage of the availability of lines of mice in which green fluorescent protein (GFP) is expressed in subsets of inhibitory cells to reveal the function and connectivity of common subtypes of auditory neurons that have been rarely studied using direct electrophysiological means. Second, we will identify mechanisms that control the duration of the inhibitory state, and focus on the role of transmitter clearance from the synaptic cleft and the promising role of GABA/glycine cotransmission in regulation of glycinergic decays. Finally, we will determine what mechanisms set whether glycine excites or inhibits postsynaptic neurons.