GENETIC LINKAGE OF AUDITORY GATING

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适合在动物和精神分裂症患者中进行研究。 一个例子是感觉信息的异常处理；精神分裂症的一个标志。 精神分裂症患者注意力不集中，并且经常被传入的感官信息淹没。 由此产生的大量输入可能会导致人格失代偿。 可以使用条件测试范式并比较对配对听觉刺激的电生理反应来评估人类和动物的感觉处理缺陷。正常人类和大多数小鼠品系对第二次刺激的反应减弱，因此，他们正在过滤或“门控”对这种刺激的反应。 精神分裂症患者、他们的一些一级亲属和某些近交系小鼠对两种刺激的反应程度相同；因此，他们不设门。 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，最近对人类和动物的研究表明烟碱受体，特别是α7亚型，参与感觉门控的调节。 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，该位置是人类 α7 受体的映射位置。 因此，数据表明α7烟碱受体可能调节人类和啮齿动物的听觉门控，但是不能排除其他系统。 在使用 2 个近交系小鼠品系的经典育种研究中，门控能力被证明是具有单基因、常染色体显性模式的遗传性状。 该提案将寻求识别小鼠基因组中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了 C3H 小鼠（门控品系）和 DBA/2 小鼠（非门控品系）之间的杂交。 我有大量关于亲本品系、F1、F2 和回交代的听觉门控数据，当前的提案将扩展这些研究，并评估小鼠 α7 烟碱受体基因附近已识别的限制性片段长度多态性 (RFLP) 与听觉门控之间的关系 (Expt. 1)。 此外，全基因组扫描将尝试将听觉门控与任何其他染色体位点联系起来（实验 2）。 另一项研究将评估听觉门控以及与 C57BL/6 小鼠（门控品系）和 DBA/2 小鼠之间第二次遗传杂交中任何基因座的联系，从而可以在与 C3H 小鼠具有相同 RFLP 的另一个遗传背景上评估 DBA/2 门控模式。 该杂交还具有重组近交 (RI) 品系，可以精确确定每个 RI 品系的门控。 听觉门控的部分差异是非遗传性的，对 RI 菌株的评估将减少这一因素。 此外，对真正的 F2 代小鼠的评估将确认 RI 品系研究中确定的位点（实验 3）。 在小鼠中鉴定出的基因座可能导致在人类中控制精神分裂症的基因的分离。 这些信息对于了解该疾病的病因和确定未来的治疗干预措施可能很重要。

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.