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

Tyler Buddell, Vladislav Friedman, Cody J Drozd and Christopher C Quinn

PLOS Genetics, 2019, vol. 15, issue 12, 1-20

Abstract: 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.Author summary: Autism is a disorder that affects neuronal development, leading to alterations in cognition and behavior. Imaging studies have revealed alterations in axonal connectivity as a key feature of autism. However, the underlying perturbations in cell biology that drive these alterations remain largely unknown. To address this issue, we have taken advantage of the Timothy syndrome mutation, a variant in a voltage-gated calcium channel that has the unusual property of causing autism with high penetrance. We identify a role for wild-type voltage-gated calcium channels in regulating axon targeting in C. elegans. Moreover, we find that two different versions of the Timothy syndrome mutation disrupt axon targeting. Our results suggest that the Timothy syndrome mutations disrupt axon targeting and behavior by interacting with genes that promote selective autophagy, the process through which cellular components are selected for degradation. These results reveal a mechanism through which variants in voltage-gated calcium channels can cause the disruptions in axonal connectivity that underlie autism.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pgen00:1008488

DOI: 10.1371/journal.pgen.1008488

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