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

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA.
² Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA.
³ Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
⁴ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA. Electronic address: spasca@stanford.edu.

PMID: 39419023
DOI: 10.1016/j.neuron.2024.09.020

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

Ji-Il Kim et al. Neuron. 2024.

. 2024 Dec 18;112(24):4048-4059.e7.

doi: 10.1016/j.neuron.2024.09.020. Epub 2024 Oct 16.

Authors

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA.
² Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA.
³ Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
⁴ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA. Electronic address: spasca@stanford.edu.

PMID: 39419023
DOI: 10.1016/j.neuron.2024.09.020

Abstract

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.

Keywords: assembloids; disease; organoids; thalamocortical; thalamus.

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Conflict of interest statement

Declaration of interests Stanford University has filed a provisional patent application covering the generation of multi-region assembloids. M.H.P. is on the Board of Directors and holds equity in Graphite Bio. M.H.P. serves on the SAB of Allogene Tx and is an advisor to Versant Ventures.

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

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

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