Table_1_Sex-Specific Social Behavior and Amygdala Proteomic Deficits in Foxp2+/− Mutant Mice.xlsx

In humans, mutations in the transcription factor encoding gene, FOXP2, are associated with language and Autism Spectrum Disorders (ASD), the latter characterized by deficits in social interactions. However, little is known regarding the function of Foxp2 in male or female social behavior. Our previous studies in mice revealed high expression of Foxp2 within the medial subnucleus of the amygdala (MeA), a limbic brain region highly implicated in innate social behaviors such as mating, aggression, and parental care. Here, using a comprehensive panel of behavioral tests in male and female Foxp2+/– heterozygous mice, we investigated the role Foxp2 plays in MeA-linked innate social behaviors. We reveal significant deficits in olfactory processing, social interaction, mating, aggressive, and parental behaviors. Interestingly, some of these deficits are displayed in a sex-specific manner. To examine the consequences of Foxp2 loss of function specifically in the MeA, we conducted a proteomic analysis of microdissected MeA tissue. This analyses revealed putative sex differences expression of a host of proteins implicated in neuronal communication, connectivity, and dopamine signaling. Consistent with this, we discovered that MeA Foxp2-lineage cells were responsive to dopamine with differences between males and females. Thus, our findings reveal a central and sex-specific role for Foxp2 in social behavior and MeA function.

在人类中，编码转录因子的FOXP2基因发生突变，与语言功能障碍及自闭症谱系障碍（Autism Spectrum Disorders，ASD）相关，此类障碍以社交互动缺陷为典型特征。然而，目前学界对于Foxp2在雄性或雌性个体社交行为中的功能仍知之甚少。我们此前在小鼠模型中的研究显示，Foxp2在杏仁核内侧亚核（medial subnucleus of the amygdala, MeA）中呈高表达——该区域作为边缘脑区，与交配、攻击、亲代抚育等先天社交行为密切相关。本研究中，我们针对雄性和雌性Foxp2+/-杂合子小鼠，采用一套全面的行为学测试组合，探究了Foxp2在MeA相关先天社交行为中的作用。我们发现，此类小鼠在嗅觉加工、社交互动、交配、攻击及亲代抚育行为中均存在显著缺陷。值得注意的是，部分缺陷表现出性别特异性的差异。为了专门探究MeA内Foxp2功能缺失所产生的影响，我们对显微切割获取的MeA组织进行了蛋白质组学分析。该分析揭示了一系列参与神经元通信、神经元连接及多巴胺信号传导的蛋白质，其表达存在潜在的性别差异。与此一致的是，我们发现MeA内的Foxp2谱系细胞可响应多巴胺信号，且雌雄个体间存在显著差异。综上，本研究结果揭示了Foxp2在社交行为及MeA功能中所发挥的核心且具有性别特异性的作用。