Neurobiology of Aggression Co-morbidity in Mouse Model of Idic15 Autism

描述(由申请人提供)：被诊断为自闭症谱系障碍(ASD)的人，除了标志性特征外，通常还患有过度攻击性(~70%的发生率)，但关于这种共同发病如何发展的知识和当前的治疗选择有限。大脑男性化是性二态区域的组织，被认为发生 在围产期大脑发育的关键时期。对于男性来说，这一时期是通过睾丸激素激增来确定的，而睾丸激素在出生后不久就会迅速下降。在大脑中，这种睾丸素主要由合成芳香酶的神经元在局部转化为雌二醇(Cyp19)。然后，雌激素激活这些神经元中的同源受体，其中核激素转录因子诱导基因表达的变化，这些变化是神经元回路功能和结构变化的基础。这些关键的荷尔蒙事件协调了这些表达芳香酶的大脑回路的男性化，为男性在以后的生活中表现出特定的行为提供了一张画布。事实上，主要是雄激素受体和次级睾丸素的激增，最终决定了这些大脑区域的活动和男性特有行为的程度，比如成年后的攻击性。最近，我们描述了人类15号等双着丝粒染色体(Idic15)的小鼠模型，该模型除了Smith等人报告的与自闭症相关的核心特征外。2011年，攻击性行为也有所增加。这是第一个已知的人类遗传性自闭症动物模型，显示出攻击性增加的共同发病率。与人类IDIC15一样，小鼠的Ube3a基因和蛋白质剂量增加了两倍，Ube3a是一种已知的核激素受体的共同激活剂，包括雌激素和雄激素的受体。鉴于这些发现，我们建议测试新的想法(适合于探索性R21拨款)，即在idic15个人和我们的小鼠模型中，过量的Ube3a会导致在大脑发育的关键时期异常强烈的雌激素受体信号，从而使成年后产生过度攻击性的大脑过度男性化。这一观点与现有的自闭症“超级男性”理论(Baron-Cohen)是一致的，但提供了一个具体的生物学解释。为了验证这一新的生物学思想，我们将进行以下研究：1)使用我们新创建的条件Ube3a在转基因小鼠上暂时诱导idic15基因剂量的Ube3a过度表达，以确定过量Ube3a产生夸张攻击行为的发育时期，并预测超雄性转录和神经解剖(表达芳香酶的神经元)脑表型。2)使用我们新创建的第二个条件性Ube3a Off转基因小鼠来诱导拯救超阳性的行为和大脑表型。抑制睾酮-芳香酶-雌激素信号通路的药物也将被测试其拯救这些表型的能力。这些研究为自闭症中的超男性大脑提供了一个生物学例子和分子机制，并解释了idic15自闭症中攻击性的增加。

DESCRIPTION (provided by applicant): Individuals diagnosed with autism spectrum disorders (ASDs) are, in addition to signature traits, often burdened by excess aggression (~70% incidence), but knowledge on how this co-morbidity develops and current treatment options are limited. Brain masculinization, the organization of sexually dimorphic regions, is thought to occur during a critical period of brain development during perinatal life. In males this period is identified by a testosterone surge that declines rapidly soon after birth. This testosterone is mostly converted to estradiol locally in the brain by neurons that synthesize the enzyme aromatase (cyp19). Estrogen then activates its cognate receptors in these neurons, where the nuclear hormone transcriptional factor induces changes in gene expression that underlie functional and structural changes in the neuronal circuits. These critical hormonal events orchestrate masculinization of these aromatase-expressing brain circuits, making a canvas for the expression of male specific behaviors later in life. Indeed it will be mostly androgen receptors and secondary testosterone surges that ultimately determine the activity of these brain regions and the extent of male-specific behaviors, such as aggression in adulthood. Recently we described a mouse model of human isodicentric chromosome 15 (idic15) that in addition to the core autism-related traits reported in Smith et al. 2011 also exhibits increased aggressive behavior. This represents the first known animal model of a human genetic autism displaying the co-morbidity of increased aggression. As in human idic15, the mice have a tripled gene and protein dosage of Ube3a, a known co- activator at nuclear hormone receptors, including those for estrogen and androgens. In the light of these findings, we propose to test the novel idea (appropriate for an exploratory R21 grant) that excess Ube3a in idic15 individuals and in our mouse model of the disorder causes abnormally strong estrogen receptors signaling during the key period of brain development to hypermasculinize the brain generating excess aggression in adulthood. The idea is congruent with existing "hypermale" theory of autism (Baron-Cohen), but provides a concrete biological explanation. To verify this new biological idea, we will perform the following studies: 1) Use our newly created conditional Ube3a ON transgenic mice for temporally-induced over- expression of the idic15 gene dosage of Ube3a to determine the developmental time period when excess Ube3a generates the exaggerated aggression behaviors and predicted hyper-male transcriptional and neuroanatomical (aromatase expressing neuron) brain phenotypes. 2) Use our second newly created conditional Ube3a OFF transgenic mice for induced rescue of the hyper-masculine behavioral and brain phenotypes. Pharmacological agents that inhibit the testosterone-aromatase-estrogen signaling pathway will also be tested for their ability to rescue these phenotypes. These studies provide a biological example and molecular mechanism for the hypermale brain in autism and explain increased aggression in idic15 autism.