Abnormalities in thalamocortical crosstalk can lead to neuropsychiatric disorders. Variants in CACNA1G, which encodes the α1G subunit of the thalamus-enriched T-type calcium channel, are associated with absence seizures, intellectual disability, and schizophrenia, but the cellular and circuit consequences of these genetic variants in humans remain unknown. Here, we developed a human assembloid model of the thalamocortical pathway to dissect the contribution of genetic variants in T-type calcium channels. We discovered that the M1531V CACNA1G variant associated with seizures led to changes in T-type currents in thalamic neurons, as well as correlated hyperactivity of thalamic and cortical neurons in assembloids. By contrast, CACNA1G loss, which has been associated with risk of schizophrenia, resulted in abnormal thalamocortical connectivity that was related to both increased spontaneous thalamic activity and aberrant axonal projections. These results illustrate the utility of multi-cellular systems for interrogating human genetic disease risk variants at both cellular and circuit level.

中文翻译：

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人类组装体揭示了丘脑皮质通路中 CACNA1G 基因变异的后果


丘脑皮质串扰异常可导致神经精神疾病。CACNA1G 编码富含丘脑的 T 型钙通道的 α1G 亚基，其变异与失神发作、智力障碍和精神分裂症有关，但这些遗传变异在人类中的细胞和回路后果仍然未知。在这里，我们开发了丘脑皮质通路的人类组装体模型，以剖析遗传变异在 T 型钙通道中的贡献。我们发现与癫痫发作相关的 M1531V CACNA1G 变体导致丘脑神经元中 T 型电流的变化，以及集合体中丘脑和皮层神经元的相关多动。相比之下，与精神分裂症风险相关的CACNA1G丢失导致丘脑皮质连接异常，这与自发丘脑活动增加和异常轴突投射有关。这些结果说明了多细胞系统在细胞和回路水平上询问人类遗传病风险变异的效用。