Dissecting the role of CaV1.2 dysfunction in the pathogenesis of autism spectrum disorder

Abstract

Autism Spectrum Disorder (ASD) is a neurological disorder characterized by repetitive, restricted behaviors, interests and activities along with a range of challenges in communication skills and social interaction. Pathway and genetic analyses have indicated a strong connection between ASD and the dysregulation of Ca2+ signaling. In particular, genetic mutations within the L-type Ca2+ channel (LTCC) have been shown to be causative of ASD. In fact, mutations within the CaV1.2 LTCC have been identified as one of the few monogenic causes of ASD, resulting in a multisystem disorder known as Timothy Syndrome (TS). TS patients harbor a single de novo point mutation within CaV1.2, which causes severe cardiac arrhythmias, long-QT syndrome and ASD. TS is one of the most penetrant genetic forms of ASD, making it an ideal model system with which to gain traction on understanding the role of Ca2+ dysfunction in ASD. Interestingly, we identified marked differences in channel gating due to distinct TS mutations. Such differences may underlie the differential phenotypes of select mutations, potentially explaining why some pathogenic mutations do not lead to ASD. To probe the effects of these mutations on neuronal function, we utilized human induced pluripotent stem cell (iPSC)-derived neurons. Patch clamp recordings of these cells yield distinct LTCC currents, enabling evaluation of the mutations in the context of a human neuron. Moreover, we utilized iPSC-derived 3D neuronal organoids to gain a deeper understanding of the effect of CaV1.2 dysfunction at a network level. Overall, as Ca2+ disruption may be a recurrent feature of ASD, studying rare mutations such as TS, may provide insight into the pathogenesis ASD beyond TS.