Convergence of schizophrenia risk genes on CALN1 disrupts human forebrain development and drives core psychotic behaviors including hallucination-like perception

Schizophrenia, a highly heritable neurodevelopmental disorder characterized by core clinical symptoms such as hallucination, remains poorly understood its polygenic pathogenesis. We selected 11 key schizophrenia risk genes and generated single-gene-knockout-precise-dorsal/ventral-forebrain-organoids via CRISPR-Cas9 system to investigate the polygenic effects of these schizophrenia risk genes on forebrain development via bulk and scRNA-sequencing, multi-electrode array recording and knockout mouse model. We found that knockout of 11 risk genes leads to different levels of deficits in human dorsal/ventral forebrain organoids. Notably, CALN1 knockout significantly impacted pathways involved in forebrain development and the set of prioritized schizophrenia risk genes. Importantly, Caln1 -KO mice exhibited a broad spectrum of schizophrenia-like behaviors, encompassing deficits in spatial memory, social ability and pre-pulse inhibition, alongside spontaneous startle behavior, head-twitch response and hallucination-like perception. At the cellular level, Caln1 -deficient mice exhibit abnormal spontaneous abrupt burst spiking in mature layer-5 pyramidal neurons of the prefrontal cortex, and snRNA-seq analysis of Caln1 −/− mice revealed severe transcriptional and gene network dysregulation in layer-5 excitatory neurons. This study reveals that CALN1 as a pivotal role in schizophrenia risk genes robustly perturb human forebrain development and cause a broad spectrum of schizophrenia behaviors in mice.