The expanded subcortical neurogenesis was accompanied by opposite changes in the CZ, where fewer mature neurons developed in schizophrenia organoids. This was shown by a significant reduction in cortical Pan-Neu intensity and was corroborated by visibly diminished Pan-Neu fibers in the schizophrenia organoids. The specific depletion of the neurons in the cortex, but not in the IZ, may reflect the loss of cortical signals that guide the cortico-petal migration, i.e. reduced cortical deposition of reelin and pioneer TBR1 neurons. The altered intracortical connectivity in schizophrenia organoids was further denoted by the changes in the orientation of the calretinin+ interneurons. Unlike the horizontal organization of calretinin+ neurites in the control cortex, the schizophrenia interneurons displayed a random directionality of neurites, indicating perturbed intercortical connectivity. The relationship between glutamatergic pyramidal neurons and GABAergic interneurons (of which calretinin-positive neurons are a subtype of GABAergic interneurons), has been suggested in relation to the development of schizophrenia in humans58. So far, attempts to count calretinin neurons in the schizophrenia brain showed lack of significant numerical changes59. Our study suggests that changes in interneuron directionality may disrupt cortical connections and communication in schizophrenia.
