Disease Development Modelled by Induced Pluripotent Cells in 3D Brain Structures

By Marcia-Ruth Ndege ‘21

GFPneuron.png

Figure 1. The 3D models can be further manipulated using gene editing tools such as CRISPR-Cas9.

The rise of three-dimensional brain structures is improving and personalizing medicine by allowing neuroscientists to closely examine the intricacies of the brain. This promising approach is centered around obtaining region-specific 3D brain cultures from individuals and assembling circuits and pathways in the samples. Sergiu Pasca, an assistant professor of Psychiatry and Behavioral Sciences at Stanford Center for Sleep Sciences and Medicine, is utilizing these models to study disease development in the central nervous system (CNS).

In one successful model, researchers used induced pluripotent cells from patients affected by macrocephaly related autism to model the dorsal and ventral domains of the brain. The model revealed an irregularity in the proportion of GABAergic interneurons, inhibitory neurons that play a vital role in neural activity and circuitry. This defect was then connected to the overexpression of a transcription factor known as FOXG1, which interferes with brain development and causes seizures and autism. A different model used cells extracted from patients with Timothy syndrome, a condition in which the heart takes a long time to recharge between beats. Forebrain structure models uncovered abnormalities in the migration of cortical interneurons. This discovery, in turn, opened a door to pharmaceutical interventions. Models of human neurons have also helped determine the specific cells in the CNS that are affected by microcephaly-related Zika virus infection, thereby facilitating the creation of drugs that reduce infection.

While these findings are extremely promising, each model has its flaws. For instance, the completed structures typically measure a maximum of 4 millimeters, which is miniscule compared to the actual size of the studied region. While there is much room for improvement, there is also a bright future for 3D brain structures in neuroscience.

References:

  1. S. Pasca, The rise of three-dimensional human brain cultures. Nature 553, 437-445 (2018). doi:10.1038/nature25032
  2. Image retrieved from: https://commons.wikimedia.org/wiki/File:GFPneuron.png
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