CACNA1C genetic variants differentially affect neuronal networks through divergent pathways

Wilkinson, Gemma, Wood, Jamie, Roivainen, Nuppu, Haddon, Josephine E. ORCID: https://orcid.org/0000-0001-5975-813X, Underwood, Jack F.G. ORCID: https://orcid.org/0000-0003-1731-6039, Hall, Jeremy ORCID: https://orcid.org/0000-0003-2737-9009 and Harwood, Adrian J. ORCID: https://orcid.org/0000-0003-3124-5169 2026. CACNA1C genetic variants differentially affect neuronal networks through divergent pathways. Biological Psychiatry Global Open Science , 100792. 10.1016/j.bpsgos.2026.100792

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Abstract

Background CACNA1C encodes the pore-forming subunit of the L-type calcium channel Cav1.2. Common variants in CACNA1C are associated with psychiatric disorders, while rare single-nucleotide variants cause CACNA1C-related disorder (CRD), a multi-system disorder with symptoms that include autism spectrum disorder (ASD), intellectual disability and seizures. However, the cellular mechanisms linking CACNA1C dysfunction to neurodevelopmental phenotypes remain poorly understood. Methods We generated isogenic CACNA1C loss-of-function (LoF) induced pluripotent stem cell (iPSC) lines and reprogrammed a line from an individual carrying a novel predicted gain-of-function (GoF) variant (p.Ala1521Pro) in CACNA1C. Neuronal activity was assessed using multi-electrode arrays (MEA), pharmacological manipulation, and gene expression analysis. Early developmental phenotypes were examined using qRT-PCR, immunocytochemistry, and RNA sequencing. Results Neurons carrying CACNA1C variants displayed opposing alterations in network dynamics, depending on variant type. Pharmacological and molecular assays indicated that these network differences were associated with dysregulated GABAergic signaling. Early developmental analysis revealed that loss of CACNA1C altered rosette morphology, CREB phosphorylation, and transcriptional programs related to axonogenesis and synaptic signaling, indicating effects on neuronal differentiation. The patient line exhibited opposing effects on rosette morphology and CREB signaling, reflecting variant-specific effects. Conclusions These findings demonstrate that Cav1.2 regulates excitatory–inhibitory balance, network organization, and aspects of neurodevelopment. Divergent effects of CACNA1C variants highlight how altered Cav1.2 signaling contributes to variable neurodevelopmental phenotypes, including ASD and epilepsy, and establish a framework for defining CACNA1C variant effects in human neurons.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine Schools > Biosciences
Publisher:	Elsevier BV
ISSN:	2667-1743
Date of First Compliant Deposit:	28 July 2026
Date of Acceptance:	15 July 2026
Last Modified:	28 Jul 2026 09:15
URI:	https://orca.cardiff.ac.uk/id/eprint/188509

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