Cortical assembloids support the development of fast-spiking human PVALB+ cortical interneurons and uncover schizophrenia-associated defects
Disruption of fast-spiking, parvalbumin positive (PVALB+) cortical interneurons is implicated in the pathogenesis of schizophrenia. However, how and when these defects emerge during development is not well understood. The protracted maturation of these cells during postnatal development has made their derivation from human pluripotent stem cells (hPSCs) extremely difficult, precluding studies on their role in neuropsychiatric diseases using hPSC-based disease models. Furthermore, the complex genetics of schizophrenia makes genetic background a confounding variable for studies using patient-specific hiPSC lines. Here we present a cortical assembloid system that supports the development of fast-spiking cortical interneurons which co-express LHX6 and PVALB, match the molecular profiles of primary PVALB+ interneurons by scRNAseq and display their distinctive electrophysiological features. The presence of PVALB+ interneurons in assembloids was correlated with gamma-band oscillatory rhythms at the network-level. We next characterized cortical interneuron development in a series of CRISPR-generated isogenic structural variants strongly associated with schizophrenia risk and identified variant-specific phenotypes both in cortical interneuron migration and in the molecular profile of PVALB+ cortical interneurons. These findings reveal plausible mechanisms on how disruption of cortical interneuron development may impact schizophrenia risk and provides an exciting human experimental platform to facilitate the study of authentic, fast-spiking cortical interneurons.