Gene discovery in a putative mouse model of ADHD

描述(由申请人提供)： 妊娠期间甲状腺水平异常可能会对大脑发育和认知产生破坏性影响。甲状腺抵抗综合征(RTH)是一种可遗传的疾病，由TRbeta基因突变引起，通常会导致甲状腺激素升高、身材矮小和心动过速。超过一半的RTH患者患有注意力缺陷多动障碍(ADHD)，男性的发病率约高出50%。虽然ADHD的病因尚不清楚，但相当多的证据表明多巴胺能和去甲肾上腺素能神经递质系统存在缺陷。正常的甲状腺系统对儿茶酚胺能系统的正常发育至关重要，甲状腺异常可导致符合ADHD的行为和神经化学特征。我们最近发现，携带人类突变的甲状腺β1受体的TRbeta转基因小鼠复制了ADHD的所有关键症状，如青少年多动、持续和选择性注意缺陷、冲动和儿茶酚胺水平降低。有趣的是，TRbeta转基因小鼠的甲状腺激素、促甲状腺激素(TSH)水平正常，TSH水平受到抑制。这是耐人寻味的，因为它增加了一种可能性，即轻度发育性甲状腺功能障碍可能导致ADHD病例的比例比之前认为的更大。除了这种疾病的核心症状外，小鼠还表现出ADHD的许多更微妙的特征，例如，成年后多动症消失，雄性的外显性强于雌性，持续注意力的缺陷随着强化水平的提高而减弱。TRbeta转基因小鼠的另一个有趣的特征是，多动表型取决于母体的基因型别，与小鼠自身的基因型别无关。这表明母亲或环境对ADHD亚型的影响可能有生物学或行为学基础。在动物模型中，复杂的人类行为障碍之间的高度相似，对于复杂的、多基因的行为障碍来说是无与伦比的。我们建议使用微阵列技术来检测野生型和转基因、雄性和雌性，以及转基因母羊的后代和野生型母羊的后代，以及幼崽、青少年和成年人的差异基因表达。TRbeta转基因小鼠模型为我们提供了一个难得的机会来发现TRbeta活性下游的基因，这些基因能够产生ADHD的所有核心症状和许多附属特征-这些基因可能在大量ADHD儿童中差异表达。此外，我们有一个前所未有的机会来发现基因表达和行为之间的关系如何根据诊断亚型、性别、治疗难治性和环境(如母体)条件而不同。

DESCRIPTION (provided by applicant): Abnormal thyroid levels during gestation can have devastating effects on brain development and cognition. Resistance to thyroid (RTH) syndrome is a heritable condition caused by mutations in the TRbeta gene that typically result in elevated thyroid hormones, short stature, and tachycardia. More than half of RTH patients have attention deficit hyperactivity disorder (ADHD), with the incidence about 50% higher among males. Although the etiology of ADHD is unknown, considerable evidence implicates deficiencies in the dopaminergic and noradrenergic neurotransmitter systems. A normally functioning thyroid system is critical for proper development of the catecholaminergic systems, and thyroid abnormalities can result in behavioral and neurochemical features consistent with ADHD. We have recently found that a TRbeta transgenic mouse bearing a human mutant thyroid beta1 receptor reproduces all of the key symptoms of ADHD, such as juvenile hyperactivity, deficits in sustained and selective attention, impulsivity, and reduced catecholamine levels. Interestingly, the TRbeta transgenic mice have normal levels of thyroid hormones, thyroid stimulating hormone (TSH), and suppression of TSH. This is intriguing because it raises the possibility that modest developmental thyroid dysfunction may contribute to a larger proportion of ADHD cases than previously thought. In addition to the core symptoms of the disorder, mice demonstrate many of the more subtle features of ADHD, e.g., the hyperactivity dissipates in adulthood, the penetrance is greater among males than among females, and the deficit in sustained attention is attenuated with greater reinforcement levels. Another interesting feature of the TRbeta transgenic mice is that the hyperactivity phenotype depends on the maternal genotype, independent of the mouse's own genotype. This suggests a possible biological or behavioral basis for maternal or environmental effects on ADHD subtypes. This high degree of analogy between complex human behavioral disorders in an animal model is unparalleled for a complex, multigenic behavioral disorder. We propose to use microarray technology to examine differential gene expression in wild-types vs. transgenics, males vs. females, and offspring of transgenic dams vs. offspring of wild-type dams, in pups, adolescents, and adults. The TRbeta transgenic mouse model provides us with a rare opportunity to discover genes downstream of TRbeta activity that are able to produce all of the core symptoms and many adjunct features of ADHD-genes that may be differentially expressed in a large number of children with ADHD. In addition, we have an unprecedented opportunity to discover how the relationship between gene expression and behavior differs according to diagnostic subtype, gender, treatment refractoriness, and environmental (e.g., maternal) conditions.