# Elucidating the molecular mechanisms behind human neurodevelopmental disorders using brain organoids

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $719,203

## Abstract

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 ou...

## Key facts

- **NIH application ID:** 10467918
- **Project number:** 1R01MH130061-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** BENNETT G NOVITCH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $719,203
- **Award type:** 1
- **Project period:** 2022-02-16 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467918

## Citation

> US National Institutes of Health, RePORTER application 10467918, Elucidating the molecular mechanisms behind human neurodevelopmental disorders using brain organoids (1R01MH130061-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10467918. Licensed CC0.

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