Both a schizophrenia susceptibility gene, NOS1AP, and an antipsychotic agent, clozapine, stunt dendrite development in human iPSC-derived neurons
Abnormal dendritic arbor development has been implicated in a number of neurodevelopmental disorders, such as autism and Rett syndrome, as well as the neuropsychiatric disorder schizophrenia. NOS1AP, a protein encoded by a schizophrenia susceptibility gene, is an intracellular factor that alters neuronal morphology and synaptic structures. Brain samples from subjects with schizophrenia have elevated levels of NOS1AP in the DLPFC, a region of the brain associated with cognitive function. Furthermore, we previously reported that NOS1AP negatively regulates dendrite branching in rat hippocampal neurons. For patients with the NOS1AP schizophrenia risk factor, the cognitive deficits could be linked to neurodevelopmental defects. To investigate the role that NOS1AP plays in human dendritic arbor development, we used human iPSC technology to generate human neurons. We found that increased protein levels of NOS1AP decrease dendrite branching in human neurons at the developmental time point when both primary and secondary branching actively occurs. Next, we tested whether an antipsychotic drug is able to restore normal dendritogenesis in these human neurons. Preliminary results suggest that the antipsychotic agent clozapine decreases dendrite branching in the developing human neurons, both alone and when in combination with increased NOS1AP protein levels. Our studies show how an in vitro model of a schizophrenia vulnerability factor could be used as a platform to screen drugs for preventative therapies. In addition, this in vitro model of human dendrite development can be used to determine whether prenatal exposure to drugs that act in the CNS produce potentially lasting adverse effects on fetal neurodevelopment.