GENETIC LINKAGE OF AUDITORY GATING

听觉门控的遗传联系

• 批准号: 6186527
• 负责人: KAREN E STEVENS
• 金额: $ 18.59万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6186527
• 关键词: auditory feedback; chromosomes; disease /disorder etiology; gene expression; genetic markers; genetic strain; genotype; laboratory mouse; linkage mapping; neural information processing; phenotype; polymerase chain reaction; restriction fragment length polymorphism; schizophrenia; sensory feedback

Schizophrenia is a disease of unknown etiology which does not occur in animals. However, some aspects of the disorder are amenable to study in both animals and schizophrenia patients. An example is abnormal processing of sensory information; a hallmark of schizophrenia. Schizophrenics concentrate poorly and are often overloaded by incoming sensory information. The resultant flood of input may lead to personality decompensation. Deficient sensory processing can be assessed in both humans and animals using a conditioning-test paradigm and comparing the electrophysiological responses to paired auditory stimuli. Normal humans and most mouse strains show a reduced response to the second stimulus, thus, they are filtering or "gating" their response to this stimulus. Schizophrenia patients, some of their first degree relatives, and certain inbred mouse strains show responses to both stimuli which are of the same magnitude; thus, they do not gate. Traditional neuroleptic treatment does not normalize the gating deficit in schizophrenics, however, recent studies in both humans and animals have demonstrated involvement of the nicotinic receptor, specifically the alpha7 subtype, in the modulation of sensory gating. In a recent study of human pedigrees, the gating deficit was shown to be linked to chromosomal position 15q13-14, the site to which the human alpha7 receptor maps. Thus, data suggest that the alpha7 nicotinic receptor may be modulating auditory gating in both humans and rodents, however, other systems cannot be ruled out. In a classical breeding study using 2 strains of inbred mice, gating capacity was shown to be a heritable trait with a single gene, autosomal dominant pattern. This proposal will seek to identify chromosomal loci in the mouse genome which are linked to the auditory gating deficit. The segregation data suggesting the single gene model used a cross between the C3H mouse (a gating strain) and the DBA/2 mouse (a non-gating strain). I have a significant volume of data on auditory gating with the parental strains, F1, F2 and backcross generations, and the current proposal would extent these studies as well as assess the relationship between an identified restriction fragment length polymorphism (RFLP), near the alpha7 nicotinic receptor gene in the mouse, and auditory gating (Expt. 1). Also, a full genome scan will attempt to link auditory gating with any other chromosomal loci (Expt. 2). Another study will assess auditory gating and linkage to any loci in a second genetic cross between C57BL/6 mice (a gating strain) and DBA/2 mice, allowing assessment of the DBA/2 gating pattern on another genetic background with the same RFLP as C3H mice. This cross also has recombinant inbred (RI) strains which allows precise determination of gating for each RI strain. Part of the variance in auditory gating is non-genetic, and assessment of RI strains will reduce this component. In addition, assessment of true F2 generation mice will confirm sites identified in the RI strain study (Expt. 3). Identified loci in mice may lead to isolation of the gene(s) controlling schizophrenia in humans. Such information could be important in understanding of the etiology of the disorder and in determining future therapeutic interventions.

精神分裂症是一种病因不明的疾病，不会发生在动物身上。然而，这种疾病的某些方面可以在动物和精神分裂症患者身上进行研究。一个例子是感觉信息的异常处理；这是精神分裂症的标志。精神分裂症患者注意力不集中，经常被传入的感官信息过载。由此产生的大量输入可能导致人格失代偿。在人类和动物中，感觉加工缺陷可以通过条件反射测试范式进行评估，并比较对配对听觉刺激的电生理反应。正常人和大多数小鼠对第二种刺激的反应减弱，因此，它们对这种刺激的反应是过滤或“门控”的。精神分裂症患者，他们的一些一级亲属，以及某些近交系小鼠对这两种刺激的反应都是相同的；因此，他们不闸门。传统的抗精神病药物治疗并不能使精神分裂症患者的门控缺陷正常化，然而，最近在人类和动物身上的研究表明，尼古丁受体，特别是alpha7亚型，参与了感觉门控的调节。在最近的一项人类谱系研究中，门控缺陷被证明与染色体位置15q13-14有关，这是人类alpha7受体所在的位置。因此，数据表明alpha7烟碱受体可能调节人类和啮齿动物的听觉门控，然而，不能排除其他系统的可能性。在一项使用2株近交系小鼠的经典育种研究中，门控能力被证明是一种单基因遗传特征，常染色体显性模式。本提案将寻求在小鼠基因组中识别与听觉门控缺陷相关的染色体位点。分离数据表明，单基因模型使用C3H小鼠（一个门控菌株）和DBA/2小鼠（一个非门控菌株）之间的杂交。我有大量关于亲本菌株、F1、F2和回交代的听觉门控的数据，目前的建议将扩展这些研究，并评估小鼠α 7烟酸受体基因附近已鉴定的限制性片段长度多态性（RFLP）与听觉门控之间的关系（见图1）。此外，全基因组扫描将试图将听觉门控与任何其他染色体位点联系起来（见图2）。另一项研究将评估C57BL/6小鼠（一种门控菌株）和DBA/2小鼠之间的第二个遗传杂交中听觉门控和与任何位点的连锁，从而评估与C3H小鼠具有相同RFLP的另一遗传背景上的DBA/2门控模式。该杂交还具有重组自交系（RI）菌株，可以精确测定每个RI菌株的门控。听觉门控的部分变异是非遗传性的，对RI菌株的评估将减少这一成分。此外，对真F2代小鼠的评估将证实RI菌株研究中发现的位点（见图3）。在小鼠中发现的基因座可能导致分离控制人类精神分裂症的基因。这些信息对于了解疾病的病因和确定未来的治疗干预措施可能是重要的。