Optogenetic treatment of social behavior in autism

描述（由申请人提供）：接触素相关蛋白样2（CNTNAP 2）的常见和罕见突变与自闭症密切相关，常染色体隐性截短突变导致超过三分之二的患者患有自闭症。然而，CNTNAP 2相关自闭症的功能连接的改变还不清楚。最近，我们的合作者证明，CNTNAP 2基因敲除小鼠模型显示GABA能中间神经元迁移异常，强烈的社会行为缺陷，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，我们提出测试这样的假设，即在自闭症的CNTNAP 2模型中，局部和远程功能性内侧前额叶皮层连接被改变，并且纠正改变的连接的光遗传学干预将改善社会行为。最后，由于已经假设γ同步是自闭症中异常皮质功能的基础，可能用作诊断和测量对治疗的反应的生物标志物，我们将测试CNTNAP 2小鼠显示mPFC和杏仁核之间的γ相干性改变，导致这些结构中特定中间神经元类型的募集改变的假设。将使用来自鉴定的锥体神经元和中间神经元的单个和成对膜片钳记录结合体外和体内特定长程投射的光遗传学刺激或沉默来测试这些假设。这些发现将指导开发针对ASD社交行为缺陷的回路特异性治疗方法。

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.