Sunday, May 11, 2025
5/11/2025
Elucidating the molecular mechanisms behind human neurodevelopmental disorders using brain organoids - PROJECT SUMMARY Neurodevelopmental and neuropsychiatric disorders are a global health problem; yet remarkably little is known about their neurological basis in humans. Consequently, treatment options remain limited. The advent of methods to direct the formation of neurons from human embryonic and induced pluripotent stem cells (collectively hPSCs) provides unprecedented opportunities to both investigate how the function of human neural circuits is subverted by neurological disease and screen for new therapies. A major step towards these goals has been realized by the development of organoid culture techniques through which hPSC can be directed to form spatially organized, brain-like structures. Thus far, brain organoids have been successfully employed to model the impact of genetic mutations and environmental pathogens that result in overt defects in brain growth. However, overall brain structure is preserved in most neurological disorders, and defects are primarily defined by alterations in neural activities. Major challenges thus remain in developing means for defining the organization and function of neural networks within organoids and using this approach to explore underlying disease mechanisms and therapeutic opportunities. In our recent work, we discovered that remarkably complex neural network activities can emerge through the creation of cortex-ganglionic eminence fusion organoids, which permits the intermixing and functional coupling of excitatory and inhibitory neurons. Using a combination of calcium sensor imaging and electrophysiological approaches, we identified that fusion organoids exhibit sustained multifrequency neural oscillations reminiscent of higher network functions seen in intact brain samples and slice cultures. We further developed a fusion organoid model for the neurodevelopmental disorder Rett syndrome and found that organoids harboring mutations in the MECP2 gene exhibit markedly abnormal neural network activities including episodes of hypersynchronous bursting, loss of low-to-mid frequency oscillatory rhythms, and abnormal appearance of epileptiform high frequency oscillations. Together, these studies illustrate the extraordinary potential for the fusion organoid platform to report both normal and dysfunctional neural network functions and recapitulate salient pathological features seen in Rett patients such as seizures. Here, we seek to address three central questions for elucidating the mechanisms underlying neural network dysfunction associated with Rett syndrome and other neurodevelopmental disorders. First, does neural network dysfunction seen in Rett syndrome organoids generated from patients harboring different mutations correlate with the nature of the mutation? Second, what is the impact of cellular mosaicism in MECP2 function on neural network activities? Third, do organoid models for different neurological diseases with a seizure component exhibit shared or distinct network dysfunction profiles? Through our studies, we will explore how brain organoids can be best utilized to determine the root causes of a range of human neuropathologies and work towards the goal of discovering new treatments.
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