An autism-causing calcium channel variant functions with selective autophagy to alter axon targeting and behavior

Common and rare variants of the CACNA1C voltage-gated calcium channel gene have been associated with autism and other neurodevelopmental disorders including schizophrenia, bipolar disorder and ADHD. However, little is known about how CACNA1C variants affect cellular processes to alter neurodevelopment. The Timothy syndrome mutation is a rare de novo gain-of-function variant in CACNA1C that causes autism with high penetrance, providing a powerful avenue into investigating the role of CACNA1C variants in neurodevelopmental disorders. Here, we use egl-19, the C. elegans homolog of CACNA1C, to investigate the role of voltage-gated calcium channels in autism. We show that an egl-19(gof) mutation that is equivalent to the Timothy syndrome mutation can alter axon targeting and affect behavior in C. elegans. We find that wildtype egl-19 negatively regulates axon termination. The egl-19(gof) mutation represses axon termination to cause axon targeting defects that lead to the misplacement of electrical synapses and alterations in habituation to light touch. Moreover, genetic interactions indicate that the egl-19(gof) mutation functions with genes that promote selective autophagy to cause defects in axon termination and behavior. These results reveal a novel genetic mechanism whereby a de novo mutation in CACNA1C can drive alterations in circuit formation and behavior.

CACNA1C电压门控钙通道基因的常见与罕见变异已被证实与自闭症及其他神经发育障碍相关，包括精神分裂症、双相情感障碍及注意缺陷多动障碍（ADHD）。然而，目前对于CACNA1C变异如何影响细胞进程以改变神经发育的分子机制仍知之甚少。蒂莫西综合征（Timothy syndrome）突变是CACNA1C基因上一种罕见的新生功能获得性变异，可通过高外显率引发自闭症，为研究CACNA1C变异在神经发育障碍中的作用提供了强有力的研究路径。本研究利用egl-19——CACNA1C在秀丽隐杆线虫（Caenorhabditis elegans）中的同源基因，探究电压门控钙通道在自闭症中的作用。实验结果显示，与蒂莫西综合征突变等效的egl-19(gof)功能获得性突变，可改变秀丽隐杆线虫的轴突靶向模式并影响其行为。研究发现，野生型egl-19对轴突终止过程具有负调控作用；egl-19(gof)突变会抑制轴突终止，引发轴突靶向缺陷，进而导致电突触定位异常以及动物对轻触刺激的习惯化行为发生改变。此外，遗传互作实验表明，egl-19(gof)突变与介导选择性自噬的基因协同发挥作用，最终引发轴突终止与行为缺陷。上述研究结果揭示了一种全新的遗传机制：CACNA1C的新生突变可通过该机制驱动神经环路形成与行为模式的改变。