By Meagan Hutchinson
Many parts of brain development are difficult for scientists to study, especially in individuals with Phelan-McDermid syndrome, since brain imaging can be tough to complete due to the hallmark clinical features. Dr. Alex Shcheglovitov from the University of Utah, who is part of our PMSF Scientific Advisory Committee (SAC), and his team have developed a way to make lab-grown models of the brain (called brain organoids) that are missing the SHANK3 gene. These brain organoids without SHANK3 are one important method of modeling the brain structure and function of individuals with Phelan-McDermid syndrome, though we all know humans do not grow in a petri dish so there are inherent limitations of this method!
This work was initially published in 2022 in Nature Communications, and found that the “mini-brains” make functional brain cells (neurons) that have the ability to send electrical signals after being grown in a dish for 5 months. In the “mini-brains” with the SHANK3 deletion, the neurons were more excitable compared to control “mini-brain” neurons. These “mini-brains” can help model early brain development, particularly in the part of the brain that eventually forms key structures that are involved in regulating learning and memory, emotions, and movement.
The new article provides a step-by-step method for other researchers to use a genome editing technique called CRISPR to make these “mini-brains.”
Key Findings:
- SHANK3 deletion “mini-brains” may be a useful method to better understand brain development and functioning in Phelan-McDermid syndrome. For example, the “mini-brains” form neural networks, meaning that they can mimic how human brain cells interact with each other and process information.
- The SHANK3 deletion “mini-brains” showed differences at the synapse (i.e., the gap where neurons “talk” to each other), one of the most replicated findings in SHANK3 mutations/Phelan-McDermid syndrome. For example, the original Wang et al., 2022 paper reported the “mini-brains” had an increase in the number of excitatory synapses, consistent with studies suggesting the brain in individuals with Phelan-McDermid syndrome may be hyper-excitable. This helps validate the SHANK3 deletion “mini-brains” as a useful model of the syndrome.
Why This Matters to Researchers:
With Dr. Shcheglovitov’s article, researchers can now use the instructions to make “mini-brains” in their own labs and further study the effects of SHANK3 in the future!
Why This Matters To Our PMSF Families:
Overall, “mini-brains” will help scientists explore how brain functioning is different in Phelan-McDermid syndrome, especially when directly testing in humans can be so challenging. Even more so, using “mini-brains” can accelerate the testing of possible new treatments. It paves the way for precision, personalized medicine by testing potential drugs on cell lines derived from individuals with Phelan-McDermid syndrome, like the ongoing work by Dr. Bridgette Moffitt of Clemson University, one of our 2023 PMSF Innovation Grant Awardees. If you haven’t listened to her podcast yet, check it out here or on YouTube here!
One Last Comment from Dr. Lauren:
Like with any pre-clinical model of Phelan-McDermid syndrome (i.e., SHANK3 knockout mouse), SHANK3 deletion “mini-brains” are not an exact replica of the condition, so we should always exercise some caution when interpreting findings. Still, we are excited that this methodology exists and grateful to Dr. Shcheglovitov’s team for being willing to share with the scientific community how other labs can use this method in the future! At the Phelan-McDermid Syndrome Foundation, we are committed to sharing exciting new scientific updates and breakthroughs as well as ensuring our community understands the limitations of the studies.