Human assembloids reveal the consequences of CACNA1G gene variants in the thalamocortical pathway | bioRxiv

Abnormalities in crosstalk between the thalamus and the cerebral cortex are thought to lead to severe neuropsychiatric disorders, such as epilepsy and psychotic disorders. Pathogenic variants in the CACNA1G gene, which encodes the α1G subunit of the thalamus-enriched T-type voltage-gated calcium channel CaV3.1, are associated with absence seizures, intellectual disability, and schizophrenia, but the cellular and circuit level consequences of these genetic variants in humans remain unknown. Here, we developed an in vitro human assembloid model of the thalamocortical pathway to systematically dissect the contribution of genetic variants in T-type calcium channels. We discovered that a CACNA1G variant (M1531V) associated with seizures led to hypersynchronous activity in the thalamus and in cortical neurons in thalamo-cortical assembloids. In contrast, CACNA1G loss, which has been associated with risk of schizophrenia, resulted in abnormal thalamocortical connectivity that was related to b

Human assembloids reveal the consequences of CACNA1G gene variants in the thalamocortical pathway | bioRxiv Skip to main content New Results Human assembloids reveal the consequences of CACNA1G gene variants in the thalamocortical pathway View ORCID Profile Ji-il Kim , View ORCID Profile Yuki Miura , View ORCID Profile Min-Yin Li , View ORCID Profile Omer Revah , View ORCID Profile Sridhar Selvaraj , View ORCID Profile Fikri Birey , View ORCID Profile Xiangling Meng , View ORCID Profile Mayuri Vijay Thete , View ORCID Profile Sergey D. Pavlov , View ORCID Profile Jimena Andersen , View ORCID P

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