Though Schizophrenia typically manifests during adolescence, evidence suggests that, for many patients, the disorder originates during development. Perhaps one of the strongest indicators of this is the fact that cognitive deficits, which represent a core component of the disease, are present in childhood, prior to the onset of the ?positive? and ?negative? symptoms that will lead to a diagnosis of schizophrenia. The cognitive symptoms of schizophrenia appear to be due to a defect in the GABAergic cells of the neocortex, cortical interneurons (cINs) of the neocortex. In fact, reductions in the expression levels of GABAergic genes in the neocortex are among the most consistently reported molecular defect in schizophrenia patients. Interestingly, evidence from human and animal models suggest that cIN dysfunction within specific regions of the neocortex is the likely cause of the cognitive deficits observed in schizophrenia patients. This raises the possibility that, in at least a subset of patients, aberrations in cIN development may be to blame for the cognitive defects observed in schizophrenia. Animal models of multiple schizophrenia-associated genomic structural variants have indicated that this may indeed be the case. However, the precise nature of cIN developmental defects as they occur in schizophrenia in humans is not known. The goal of the research project proposed herein is to unmask fundamental molecular and cellular cIN deficiencies during neocortical development in a human integrated neocortical organoid. Integrated cortical organoids and spheroids hold the promise of modeling complex diseases in a 3D culture which closely mimics the human cortex. The separate patterning and eventual aggregation of dorsal and ventral forebrain organoids allows the ventral derived cINs to migrate into the dorsal forebrain organoid and integrate with the locally born pyramidal neurons (PNs) in a manner analogous to how these structures develop in vivo. In my first proposed aim of this study, I will use schizophrenia associated genomic structural variants to define migration and distribution defects that occur during cIN integration into the dorsal forebrain in an integrated neocortical organoid. As my final aim, I will utilize integrated neocortical organoids to uncover schizophrenia- associated molecular defects present early in neurodevelopment which contribute to the disease. The completion of the aims proposed in this project will lead to the establishment of a reliable in vitro model of the human neocortex and provide potentially therapeutically relevant insights into aberrant development processes in schizophrenia.
One of the most consistent findings in schizophrenia patients are defects in cortical interneurons which control the high frequency neural oscillations often disrupted in the disease. Convergent lines of evidence also suggest a neurodevelopmental origin of schizophrenia in many patients. Here, I propose to utilize a refined human neocortical organoid system to identify neurodevelopmental cellular and molecular defects in cortical interneurons that contribute to schizophrenia.
