Functional impact of the psychiatric risk gene CACNA1C in human iPSC-derived microglia
Final Report Abstract
Psychiatric disorders such as major depression, bipolar disorder, schizophrenia, and autism are highly prevalent chronic diseases. However, their underlying pathophysiology is still largely unknown. Genomic studies have identified single nucleotide polymorphisms (SNPs) in the CACNA1C gene that are robustly associated with all of these major psychoses. Among these is the main non-coding risk SNP rs1006737. Beyond that, a gain-of-function mutation in CACNA1C has been described, which causes a multiorgan phenotype including severe cardiac arrhythmias, immune deficiency, cognitive abnormalities, and autism, named Timothy syndrome (TS). Immune alterations, e.g. due to maternal infections, and the involvement of their primary mediators in the brain, the microglia, have also been reported for psychiatric disorders. Based on this, we functionally studied microglia and microglia-containing brain organoids derived from iPSC lines originating from schizophrenia patients and carrying the CACNA1C rs1006737 risk SNP variant. LPS-stimulated microglia from CACNA1C risk SNP carriers showed increased calcium influx after depolarization as well as impaired cytokine release compared to controls. Moreover, cortical organoids differentiated from these lines exhibited higher baseline and NMDA-induced neuronal firing rates. Additionally, isogenic lines were generated that are CRISPR-edited on the CACNA1C gene for the SNP rs1006737 (risk A/A) and the TS point mutation G406R and will be used to validate the findings from the patient lines. The obtained results contribute to elucidating how microglial function is affected by the selected CACNA1C risk variants, how these changes compromise microglia-neuron interactions, thereby impairing neuronal activity and function. Overall, this study adds to a better understanding of the role microglia play in the pathogenesis and/or progression of CACNA1C-associated psychiatric disorders.
Publications
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EMBO/EMBL Symposium ‘Organoids: modelling organ development and disease in 3D culture’ 18.-21.10.2023 in Heidelberg, Germany: Poster and selection for Flash Talk presentation ‘Generation and characterization of microglia-containing human forebrain assembloids’
Susanne Michels
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4th In-Vitro 2D & 3D Neuronal Networks MxW Summit 8.-10.04.2024 in Zurich, Switzerland: Poster ‘Generation and characterization of microglia-containing human forebrain assembloids’
Susanne Michels
