Neuropsychiatric disorders share susceptibility genes, suggesting a common origin. One such gene is CNTNAP2 encoding contactin-associated protein 2 (CASPR2), which harbours mutations associated to autism, schizophrenia, and intellectual disability. Antibodies targeting CASPR2 have also been recently described in patients with several neurological disorders, such as neuromyotonia, Morvan's syndrome, and limbic encephalitis. Despite the clear implication of CNTNAP2 and CASPR2 in neuropsychiatric disorders, the pathogenic mechanisms associated with alterations in CASPR2 function are unknown. Here, we show that Caspr2 is expressed in excitatory synapses in the cortex, and that silencing its expression in vitro or in vivo decreases the synaptic expression of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and the amplitude of AMPA receptor-mediated currents. Furthermore, Caspr2 loss of function blocks synaptic scaling in vitro and experience-dependent homoeostatic synaptic plasticity in the visual cortex. Patient CASPR2 antibodies decrease the dendritic levels of Caspr2 and synaptic AMPA receptor trafficking, and perturb excitatory transmission in the visual cortex. These results suggest that mutations in CNTNAP2 may contribute to alterations in AMPA receptor function and homoeostatic plasticity, and indicate that antibodies from anti-CASPR2 encephalitis patients affect cortical excitatory transmission.

中文翻译：

---

遗传或抗体介导的自闭症相关CASPR2丧失后，AMPA受体功能被破坏。

神经精神疾病共享易感基因，提示其共同起源。一种这样的基因是编码接触蛋白相关蛋白2（CASPR2）的CNTNAP2，它具有与自闭症，精神分裂症和智力障碍相关的突变。最近，在患有几种神经系统疾病的患者中也描述了靶向CASPR2的抗体，这些患者患有神经肌强直，Morvan综合征和边缘性脑炎。尽管CNTNAP2和CASPR2在神经精神疾病中有明确的含义，但与CASPR2功能改变有关的致病机制尚不清楚。在这里，我们显示Caspr2在皮层的兴奋性突触中表达，并且在体外或体内沉默其表达会降低α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）受体的突触表达和AMPA受体介导的电流幅度。此外，Caspr2的功能丧失在体外会阻止突触缩放，并在视皮层中具有经验依赖性的稳态突触可塑性。患者CASPR2抗体降低了Caspr2的树突水平和突触AMPA受体的运输，并扰乱了视觉皮层中的兴奋性传递。这些结果表明，CNTNAP2中的突变可能有助于AMPA受体功能的改变和均相可塑性，并表明来自抗CASPR2脑炎患者的抗体会影响皮层兴奋性传递。Caspr2的功能丧失在体外会阻止突触缩放，并在视皮层中具有经验依赖性的恒静态突触可塑性。患者CASPR2抗体降低了Caspr2的树突水平和突触AMPA受体的运输，并扰乱了视觉皮层中的兴奋性传递。这些结果表明，CNTNAP2中的突变可能有助于AMPA受体功能的改变和均相可塑性，并表明来自抗CASPR2脑炎患者的抗体会影响皮层兴奋性传递。Caspr2的功能丧失在体外会阻止突触缩放，并在视皮层中具有经验依赖性的恒静态突触可塑性。患者CASPR2抗体降低了Caspr2的树突水平和突触AMPA受体的运输，并扰乱了视觉皮层中的兴奋性传递。这些结果表明，CNTNAP2中的突变可能有助于AMPA受体功能的改变和均相可塑性，并表明来自抗CASPR2脑炎患者的抗体会影响皮层兴奋性传递。