Optogenetic treatment of social behavior in autism

描述(由申请人提供)：接触蛋白相关蛋白样2(CNTNAP2)的常见和罕见突变与自闭症密切相关，常染色体隐性截断突变导致超过三分之二的患者患有自闭症。然而，CNTNAP2相关自闭症背后的功能连接变化尚不清楚。最近，我们的合作者证明，CNTNAP2基因敲除的小鼠模型显示GABA能神经元间迁移异常、强健的社会行为缺陷、重复行为、沟通问题和癫痫发作，准确地模拟了人类的状况。在这里，我们建议测试这一假设，即在CNTNAP2自闭症模型中，局部和远程功能性前额叶皮质连通性发生改变，并且纠正改变的连通性的光遗传干预将改善社会行为。最后，由于伽马同步被假设为自闭症异常皮质功能的基础，潜在地作为诊断和衡量治疗反应的生物标记物，我们将检验CNTNAP2小鼠显示mPFC和杏仁核之间的伽马一致性改变的假设，导致这些结构中特定中间神经元类型的改变招募。这些假说将通过识别的锥体和中间神经元的单个和成对的膜片钳记录，结合体外和体内特定的长期投射的光遗传刺激或沉默来验证。这些发现将指导针对ASD社会行为缺陷的回路特异性治疗的发展。

DESCRIPTION (provided by applicant): Common and rare mutations in contactin-associated protein-like 2 (CNTNAP2) are strongly linked to autism, with autosomal recessive truncating mutations resulting in autism in more than two-thirds of patients. However the alterations in functional connectivity underlying CNTNAP2-associated autism are not understood. Recently our collaborators demonstrated that a knockout mouse model of CNTNAP2 shows GABAergic interneuron migration abnormalities, robust social behavioral deficits, repetitive behaviors, communication problems, and seizures, accurately modeling the human condition. Here we propose to test the hypothesis that local and long- range functional medial prefrontal cortical connectivity is altered in the CNTNAP2 model of autism and that optogenetic interventions that correct the altered connectivity will improve social behavior. Finally, as gamma- synchronization has been hypothesized to underlie the abnormal cortical function in autism, potentially serving as a biomarker for diagnosis and gauging response to treatment, we will test the hypothesis that CNTNAP2 mice show altered gamma coherence between mPFC and amygdala, leading to altered recruitment of specific interneuron types in these structures. These hypotheses will be tested using single and paired patch clamp recordings from identified pyramidal and interneurons in combination with optogenetic stimulation or silencing of specific long-range projections, both in-vitro and in-vivo. These discoveries will guide the development of circuit-specific treatments for social behavioral deficits in ASD.