Human assembloids reveal the consequences of CACNA1G gene variants in the thalamocortical pathway
Open accessAbstract
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.
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CACNA1G loss-of-function mutations are associated with schizophrenia and intellectual disability.
“The thalamus-enriched voltage-dependent calcium channel CaV3.1 encoded by the Wnt target CACNA1G is the key mediator of thalamocortical connectivity, and putative loss-of-function mutations of CACNA1G have been associated with schizophrenia and intellectual disability [65–67].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [67]
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- Authors
- Kim, J.-I., Miura, Y., Li, M.-Y., Revah, O., Selvaraj, S., Birey, F., Meng, X., Thete, M. V., Pavlov, S. D., Andersen, J., Pașca, A. M., Porteus, M. H., Huguenard, J. R., & Pașca, S. P.
- Affiliations
- Stanford Medicine (US)
- Stanford University (US)
- Corresponding author
- Pașca, Sergiu P.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2024-12
- Volume
- 112
- Issue
- 24
- Pages
- 4048-4059.e7
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W4403467459
- Cited by
- 59
- References
- 8
- Citations by year
- 2026: 27 · 2025: 22 · 2024: 10
- FWCI
- 8.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 382 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Stanford University
- Wu Tsai Neurosciences Institute, Stanford University
- New York Stem Cell Foundation
- Stanford Maternal and Child Health Research Institute
- Triangle Arts Association
- National Research Foundation of Korea
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- CACNA1G, T-type calcium channels, thalamocortical circuits, absence seizures, schizophrenia, intellectual disability, thalamic neurons, axonal projections, neuronal hyperactivity, genetic risk variants, neuropsychiatric disorders
- MeSH terms
- Cerebral Cortex, Female, Humans, Male, Neural Pathways, Neurons, Thalamus, Genetic Variation, Calcium Channels, T-Type
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