Aberrant pace of cortical neuron development in brain organoids from patients with 22q11.2 deletion syndrome-associated schizophrenia

Abstract

Adults and children afflicted with the 22q11.2 deletion syndrome (22q11.2DS) exhibit cognitive, social, and emotional impairments, and are at significantly heightened risk for schizophrenia (SCZ). The impact of this deletion on early human brain development, however, has remained unclear. Here we harness organoid models of the developing human cerebral cortex, cultivated from subjects with 22q11.2DS and SCZ, as well as unaffected control samples, to identify cell-type-specific developmental abnormalities arising from this genomic lesion. Leveraging single-cell RNA-sequencing in conjunction with experimental validation, we find that the loss of genes within the 22q11.2 locus leads to a delayed development of cortical neurons. This impaired development was reflected in an increased proportion of actively proliferating neural progenitor cells and a reduced fraction of more mature neurons. Furthermore, we identify perturbed molecular imprints linked to neuronal maturation, observe the presence of sparser neurites, and note a blunted amplitude in glutamate-induced Ca2+ transients. The aberrant transcription program underlying impaired development contains molecular signatures significantly enriched in neuropsychiatric genetic liability. MicroRNA profiling and target gene investigation suggest that microRNA dysregulation due to DGCR8 deficiency may drive perturbations of genes governing the pace at which maturation unfolds. Using protein-protein interaction network analysis we define complementary effects stemming from other genes residing within the deleted locus. Our study uncovers reproducible neurodevelopmental and molecular alterations resulting from 22q11.2 deletions, with findings that could advance disease modeling and drive the development of therapeutic interventions.