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相关自闭症的功能连接改变尚不清楚。最近，我们的合作者证明了CNTNAP2敲除小鼠模型显示gaba能中间神经元迁移异常，强大的社会行为缺陷，重复行为，沟通问题和癫痫发作，准确地模拟了人类的情况。在此，我们提出验证以下假设：在自闭症的CNTNAP2模型中，局部和远程功能性内侧前额叶皮层连通性发生了改变，矫正这种改变的连通性的光遗传学干预将改善社会行为。最后，由于伽马同步已被假设为自闭症皮质功能异常的基础，可能作为诊断和衡量治疗反应的生物标志物，我们将验证CNTNAP2小鼠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募集改变。这些假设将在体外和体内使用单个和成对膜片钳记录已识别的锥体和中间神经元，结合光遗传刺激或特定远程投射的沉默。这些发现将指导针对ASD社会行为缺陷的电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.