Defining the molecular mechanisms of sex differences in cognitive function

摘要 神经发育障碍(NDDS)，如智力障碍(ID)和自闭症谱系障碍 (ASD)在男性中比在女性中更常见。尽管NDDS的诊断频率在 对于男性来说，这些疾病中潜在的性别偏见的分子机制仍然未知。直到最近，性 在数据分析中没有被常规考虑，女性经常被排除在行为分析之外 一起做实验。同时，几十年来，大多数被确认为NDDS的基因都在X染色体上 因为在X连锁家系中识别连锁区域相对容易，导致小鼠模型 只对一种性别进行了研究。因此，在NDDS的临床前动物模型中对性别差异的测试一直是 有限的。 我们的工作引入了缺乏卷曲线圈和含有1a(Cc2d1a)的C2结构域的小鼠作为一种新的小鼠 NDDS中分子和行为性别特异性缺陷的模型。我们发现CC2D1a功能丧失 (LOF)突变导致人类ASD、ID和癫痫发作，Cc2d1a基因敲除(KO)雄性小鼠表现出 人类表型的行为特征，包括认知和社交缺陷、多动和焦虑。 相比之下，我们的初步数据显示，雌性KO小鼠只存在较轻微的认知缺陷。Cc2d1a 由于上游PKA的失调，KO雄性也表现出性别特异性的CREB激活减少 路径。这些发现增加了男性和女性使用不同分子的可能性 为相同的行为编码信息和构建神经元电路的策略，以及在 导致了我们的假设，CC2D1A以性别特异性的方式调节CREB信号 与性别相关的行为缺陷。 这项提议的总体目标是证明我们的假设。在具体目标1中，我们将探索形态， 雄性和雌性Cc2d1a KO小鼠的生理和行为差异与 CREB信号的减少。在特定的目标2中，我们将调节PKA/CREB通路，以证明所有 这些表型通过性别特异性CREB信号缺陷联系在一起。最后，在具体目标3中，我们将 探索性别特异性CC2D1A信号转导的分子机制。如果成功，我们的研究将 鉴定CREB信号调节和连接分子和细胞的新的性二态机制 行为缺陷。我们的发现将具有非常重要的意义，因为他们将建立ID/ASD基因CC2D1A 作为大脑中性别特异性信号的关键调节器。

Abstract Neurodevelopmental disorders (NDDs), such as Intellectual Disability (ID) and Autism Spectrum Disorder (ASD) are more prevalent in males than females. Despite the fact the NDDs are diagnosed more frequently in males, the molecular mechanisms underlying sex bias in these disorders are still unknown. Until recently, sex had not been routinely considered in data analysis, and females were often excluded from behavioral experiments altogether. In parallel, for decades most genes identified for NDDs were on the X chromosome because of the relative ease to identify linkage regions in X-linked pedigrees, leading to mouse models that were studied only in one sex. Thus, testing of sex differences in preclinical animal models of NDDs has been limited. Our work introduces mice deficient for Coiled-coil and C2 domain containing 1a (Cc2d1a) as a novel mouse model for molecular and behavioral sex-specific deficits in NDDs. We found that CC2D1A loss of function (LOF) mutations cause ASD, ID and seizures in humans, and that Cc2d1a knock-out (KO) male mice display behavioral features of the human phenotype, including cognitive and social deficits, hyperactivity and anxiety. In contrast, our preliminary data show that female KO mice only present with milder cognitive deficits. Cc2d1a KO males also display a sex-specific reduction in CREB activation due a disregulation of the upstream PKA pathway. These findings raise the possibility that males and females may use different molecular strategies for encoding information and building neuronal circuits for the same behaviors, and in particular lead to our hypothesis that CC2D1A regulates CREB signaling in a sex-specific manner leading to sex-specific behavioral deficits. The overall goal of this proposal is to prove our hypothesis. In Specific Aim 1 we will explore morphological, physiological and behavioral differences between male and female Cc2d1a KO mice which correlate with reduction in CREB signaling. In Specific Aim 2 we will modulate the PKA/CREB pathway to demonstrate that all these phenotypes are connected by a sex-specific CREB signaling defect. Finally, in Specific Aim 3 we will explore the molecular mechanisms underlying sex-specific CC2D1A signaling. If successful our studies will identify a novel sexually dimorphic mechanisms for CREB signaling regulation and link molecular and cellular deficits to behavior. Our findings will be highly significant as they will establish the ID/ASD gene CC2D1A as a critical regulator of sex-specific signaling in the brain.