REELIN DEFICIENCY--MODEL FOR SCHIZOPHRENIA VULNERABILITY

描述：(改编自《调查者摘要》)端脑 众所周知，结构遵循异常复杂的胚胎学过程。 在发育过程中，RELN起着关键的信号作用。在这个项目中，我们 想要确定在出生后和成年小鼠中是否存在遗传性RELN缺陷 (RELN单倍体不足)导致进行性和 脑区特异性异常及部分异常是否存在 类似于对精神分裂症患者大脑变化的讽刺 病人。我们选择了杂合的卷轴突变体(rl+/-)小鼠作为 RELN单倍体功能不全模型。在初步实验中，我们已经证明 在成年rl+/-小鼠中，除了RELN表达低于正常外， 是一系列显微解剖和神经生理学异常 让人想起精神分裂症。因此，我们建议1)比较RELN是否 Rl+/-和野生型(Wt)小鼠的表达和神经元定位相似； 2)确定RELN单倍体不足是否会引起 RELN单倍体功能不全与皮质改变的关系 GABA能中间神经元分布、GAD67表达减少及 神经纤维密度的降低；3)研究是否有进展 随着年龄的变化，或者这些变化是否仅限于皮质或存在 精神分裂症患者的其他大脑区域；以及4)检查 RELN单倍体功能不全是一个易患青春期前期的易感性因素 小鼠的行为和显微解剖异常的发生率时 暴露在有害的侮辱中，如社交孤立压力。 尽管推测RELN单倍体功能不全与表观遗传学的相互作用 精神分裂症患者中发生的因素可能与这些因素不同 在社交隔离的小鼠身上进行操作，对小鼠模型的研究可能会揭示 RELN可能破坏的神经发育机制 精神分裂症患者大脑的缺陷。对RELN的理解 成人大脑中的表达调控在设计中可能非常重要 用来纠正RELN脑功能不全和减少 与此缺陷相关的行为和显微解剖异常。

DESCRIPTION: (Adapted from the Investigator's Abstract) Telencephalic brain structures are known to follow an unusually complex course of embryological developmental in which RELN plays a pivotal signaling role. In this project, we want to establish whether in postnatal and adult mice genetic RELN deficiency (RELN haploinsufficiency) leads to the expression of progressive and region-specific brain abnormalities and whether some of the abnormalities resemble caricatures of the alterations observed in the brain of schizophrenic patients. We have selected the heterozygous reeler mutant (rl +/-) mouse as a model of RELN haploinsufficiency. In preliminary experiments we have shown that in adult rl +/- mice, in addition to a lower than normal RELN expression there are a number of microanatomical and neurophysiological abnormalities reminiscent of schizophrenia. Thus, we propose to 1) compare whether RELN expression and neuronal location are similar in rl +/- and wild-type (wt) mice; 2) determine whether RELN haploinsufficiency elicits changes in the relationship existing between RELN haploinsufficiency and altered cortical distribution of GABAergic interneurons, decrease of GAD67 expression and decrease in neuropil density; 3) study if there is a progression of these changes with age, or if these changes are restricted to cortex or are present in other brain areas that are also affected in schizophrenia; and 4) examine if RELN haploinsufficiency is a vulnerability factor that predisposes peripubertal mice to an incidence of behavioral and microanatomical abnormalities when exposed to noxious insults such as social isolation stress. Although the putative interaction of RELN haploinsufficiency with epigenetic factors occurring in schizophrenic patients probably differs from the factors operative in socially isolated mice, study of the murine model may reveal those mechanisms of neurodevelopment that are likely to be disrupted by RELN deficiency in the brain of schizophrenic patients. The understanding of RELN expression regulation in adult brain may be of great importance in the design of pharmacological tools to correct RELN brain insufficiency and to reduce the behavioral and microanatomical abnormalities associated to this deficiency.