Researchers have utilized advanced technology to gain insights into the neurodevelopmental origins of schizophrenia, a severe neuropsychiatric disease. In one study, scientists grew brain organoids derived from patients’ skin cells and discovered persistent axonal dysregulation in individuals with schizophrenia. In a separate study, researchers focused on a schizophrenia risk gene called CYFIP1 and revealed its potential involvement in microglia, immune cells of the brain that influence synaptic pruning, an essential process for brain health.
Schizophrenia is a complex disease that is poorly understood and treated. It typically begins during adolescence or early adulthood and is believed to involve abnormalities in neurodevelopment. However, studying human brain tissue during the critical prenatal period has been challenging due to limited accessibility. Two studies published in Biological Psychiatry utilize new technology to investigate schizophrenia in models of early human brain development.
The first study employed three-dimensional brain organoids, which mimic fetal brain development. The researchers collected skin cells from 14 schizophrenia patients and 14 healthy controls and converted them into induced pluripotent stem cells (iPSCs). These iPSCs were then manipulated to develop into brain-like cortical spheroids. Comparative analysis revealed differences in gene expression between organoids grown from patients and controls, with genes associated with neuronal axons standing out as a prominent group. The researchers observed persistent axonal dysregulation throughout the development of the organoids, suggesting its early contribution to schizophrenia risk.
The second study focused on a specific genetic risk locus known as 15q11.2, which contains four genes associated with schizophrenia. One of these genes, CYFIP1, has been linked to synaptic function, increased risk for neurodevelopmental disorders including schizophrenia and autism, and high expression in microglia. Microglia are involved in critical processes such as synaptic pruning, which shapes healthy brain development. The researchers used CRISPR technology to remove functional CYFIP1 from microglia-like cells derived from induced pluripotent stem cells. The study found that the loss of CYFIP1 function affected microglial behavior and function, potentially disrupting synaptic pruning, neuronal maintenance, and brain development. Variations in CYFIP1 have been associated with autism and schizophrenia.
The complexity of schizophrenia involves increased elimination of glutamatergic synapses during development and disturbances in the signaling properties of these synapses. These disturbances can disrupt circuit function, leading to symptoms and cognitive impairments associated with schizophrenia. Understanding the role of risk genes in brain diseases requires investigating beyond neurons and focusing on relevant cell types. Discovering risk loci is just the first step, and unraveling the precise functions of the genes in particular cell types is crucial for developing effective treatments.
In conclusion, these studies shed light on the molecular basis of schizophrenia during early brain development. The use of brain organoids and investigations of specific genetic risk loci provide valuable insights into the neurodevelopmental origins of schizophrenia. By identifying persistent axonal dysregulation and uncovering the role of CYFIP1 in microglia, researchers are expanding our understanding of the complex mechanisms underlying this debilitating disorder.
