The Glycine Receptor in a Rat Tinnitus Model: A Possible Therapeutic Target

描述(申请人提供)：慢性耳鸣是一种幻觉的听觉感觉，高达15%的人口经历。2%到10%的耳鸣患者通常会经历持续的高频振铃或嘶嘶声，其响度足以严重影响他们的生活质量(Cooper，1994)。耳鸣已被发现随着年龄的增长而增加。因此，由于寿命延长和娱乐性噪音暴露，耳鸣的发生率可能会增加。目前关于耳鸣发生的许多想法都围绕着某些中枢听觉结构中自发活动和神经过度活动的出现。一个与其他感觉系统的研究结果类似的工作假说表明，部分去传入会导致中枢变化，通常涉及到抑制性神经传递的改变。部分外周听觉去传入可引起耳鸣，同时耳蜗背核(DCN)选择性丧失抑制性甘氨酸能功能。拟议的研究将检查衰老对有耳鸣行为证据的大鼠的功能和分子神经化学影响。初步结果发现，在有耳鸣行为证据的大鼠DCN中，与年龄和噪声暴露相关的甘氨酸受体和神经营养因子神经化学改变。拟议的研究将比较年轻和老年对照组以及年轻和老年暴露于声音中的大鼠与耳鸣的行为证据之间的功能和分子神经化学变化。具体地说：1)信息和蛋白质的定量测量将被用来检测甘氨酸受体、支架蛋白、地理卟啉和保护性神经营养因子BDNF组成的亚单位的变化；2)来自DCN梭形细胞的记录将平行于行为学研究/间隙检测，并检查抑制反应特性和甘氨酸受体的敏感性；3)定量受体结合将被用于检测甘氨酸和神经营养因子受体药理学的变化。这些研究的结果将提供有关耳鸣相关的甘氨酸神经传递的变化以及在耳鸣动物模型中可能的神经营养素保护的新信息。了解衰老对与甘氨酸和脑源性神经营养因子受体(TrkB)功能相关的神经化学改变的影响，可能有助于为治疗耳鸣的新型选择性药物的开发和测试确定独特的靶点。

DESCRIPTION (provided by applicant): Chronic tinnitus is a phantom auditory sensation experienced by up to 15% of the population. Between 2 and 10% of the tinnitus population typically experience a continuous high frequency ringing or hiss sufficiently loud to impact severely on their quality of life (Cooper, 1994). Tinnitus has been found to increase with aging. Thus, the incidence of tinnitus is likely to increase due to increased longevity and recreational noise exposure. Much of the present thinking regarding the generation of tinnitus revolves around the appearance of spontaneous activity and neural hyperactivity in certain central auditory structures. A working hypothesis which parallels findings in other sensory systems suggests that partial deafferentation leads to central changes, generally involving altered inhibitory neurotransmission. Partial peripheral auditory deafferentation may produce tinnitus, coincident with a selective loss of inhibitory glycinergic function in the dorsal cochlear nucleus (DCN). Proposed studies will examine the functional and molecular neurochemical impact of aging in rats with behavioral evidence of tinnitus. Preliminary results find age and noise-exposure related changes in glycine receptor and neurotrophic factor neurochemistry in DCN of rats with behavioral evidence of tinnitus. Proposed studies will compare functional and molecular neurochemical changes between young and aged controls, and young and aged sound-exposed rats with behavioral evidence of tinnitus. Specifically: 1) quantitative measures of message and protein will be used to examine changes in the subunit make up of the glycine receptor, the scaffolding protein, gephyrin, and the protective neurotrophin BDNF; 2) recordings from DCN fusiform cells will parallel behavioral studies/gap detection and examine inhibitory response properties and glycine receptor sensitivity and 3) quantitative receptor binding will be used to examine changes in glycine and neurotrophin receptor pharmacology. Findings from these studies will provide new information regarding tinnitus-related changes in glycine neurotransmission and possible neurotrophin protection in an animal model of tinnitus. Understanding the impact of aging on tinnitus-related changes in neurochemistry related to glycine and the BDNF receptor (TrkB) function might help define unique targets for the development and testing of novel selective drugs for the treatment of tinnitus.