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

描述（由申请人提供）：被诊断患有自闭症谱系障碍（ASD）的个体，除了签名特征外，还经常受到过度攻击的负担（约70%的发病率），但关于这种共病如何发展的知识和目前的治疗选择是有限的。大脑的男性化，即两性异形区域的组织，被认为发生在 处于大脑发育的关键时期在男性中，这一时期是通过睾丸激素激增来确定的，但在出生后不久就会迅速下降。这种睾酮主要在大脑中由合成芳香酶（cyp 19）的神经元局部转化为雌二醇。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中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，为以后生活中男性特定行为的表达提供了画布。事实上，最终决定这些大脑区域的活动和男性特有行为（如成年期的攻击行为）程度的主要是雄激素受体和继发性睾酮激增。 最近，我们描述了一种人类等双着丝粒染色体15（idic 15）的小鼠模型，除了Smith等人2011年报道的核心自闭症相关性状外，该模型还表现出攻击行为增加。这代表了第一个已知的人类遗传性自闭症动物模型，显示了增加的攻击性的共病性。与人类idic 15一样，小鼠具有三倍的Ube 3a基因和蛋白质剂量，Ube 3a是核激素受体（包括雌激素和雄激素受体）的已知共激活剂。根据这些发现，我们建议测试新的想法（适合探索性R21补助金），即在idic 15个体和我们的小鼠模型中，过量的Ube 3a在大脑发育的关键时期导致异常强烈的雌激素受体信号传导，从而使大脑过度男性化，在成年期产生过度的攻击性。这个想法与现有的自闭症“超男性”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想法，我们将进行以下研究：1）使用我们新创建的条件性Ube 3a ON转基因小鼠用于暂时诱导的idic 15基因剂量的Ube 3a的过表达，以确定过量Ube 3a产生夸张的攻击行为和预测的超雄性转录和神经解剖（芳香酶表达神经元）脑表型的发育时间段。2)使用我们第二个新创建的条件性Ube 3a OFF转基因小鼠诱导拯救超阳性行为和脑表型。还将测试抑制睾酮-芳香化酶-雌激素信号传导途径的药理学试剂拯救这些表型的能力。这些研究为自闭症患者的过度男性化大脑提供了一个生物学例子和分子机制，并解释了idic 15自闭症患者的攻击性增加。

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.