Brain Organoids Reveal New Targets for Autism Treatment

This blog post simplifies and expands on an article posted by Scripps Research. It explores parts of this research paper.

A Brain Organoid is a scaled down version of a real brain, only composed of one million or so cells. It reflects the inter-cell relationships and communication that regular sized brains also exhibit. Think of Brain Organoids as a model brain that we can ethically experiment on. 

This is a six-well plate of Brain Organoids grown from stem cells. Picture taken by University of California Television: https://www.youtube.com/watch?v=lwReDWWMU0E

The Role of MEF2C Gene is Brain Development:

This research explored the inner workings of a controller gene called MEF2C. This is called a controller gene because this gene regulates other genes responsible for proper brain development, rather than simply producing its own protein. Any debilitating mutation in this gene can cause a condition called MEF2C Haploinsufficiency Syndrome (MHS), a form of autism linked to severe intellectual disability due to a change in the way the brain developed.

This developmental anomaly can be detected using electroencephalography (a machine that detects electric signals in the brain) where we see more excitatory neurons activating than inhibitory neurons, a phenomena called Network-level hyper-excitability.

Understanding the role of MEF2C is crucial for unraveling the complexities of brain development and associated disorders. To make the link between Network-level hyper-excitability and the MEF2C gene, scientists at Scripps Research in La Jolla, CA collected fibroblasts, or skin cells, from patients with MHS and reverse engineered them back into stem cells. From here they were differentiated into neuron cells and then grown into brain organoids that were genetic representations of each patient. Both the actual brain of the MHS patients and the brain organoids exhibited characteristics of Network-level hyper-excitability. (Think about what other conditions and diseases brain organoids can be used to model.)

What does the MEF2C gene do?

“Transcriptomic analysis of MHS hiPSC-derived neurons revealed down regulation of MEF2C target genes involved in neuronal differentiation and synaptic function.”

Let's simplify: This means that when the MEF2C gene is mutated (as in patients with MHS), the researchers saw that many other genes that depend on MEF2C were less active.

This balance of excitatory and inhibitory neurons is dictated by the MEF2C gene. It does this by controlling hundreds of other genes that code for proteins, and even a few that code for microRNAs. These microRNAs are used to control gene expression and thereby dictate whether a developing neuron cell will be inhibitory or excitatory.

This image describes the differences between the mutated and non-mutated MEF2C Gene pathways and how they result in abnormal or normal brain development.

When tested, patients with MHS are found to have depleted levels of a few certain types of microRNAs, and when their brain organoids were artificially provided more of these miRNAs, they developed more normally.

Armed with this knowledge, researchers are working on a new drug called NitroSynapsin which could repair the imbalance of neuron types.

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Recommended research topics to continue your exploration:

• Brain Organoids

• MicroRNAs

• Human Induced Pluripotent Stem Cells