# Modeling ASD-linked genetic mutations in 3D human brain organoids

> **NIH NIH R01** · HARVARD UNIVERSITY · 2024 · $849,543

## Abstract

Project summary / Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose underlying mechanisms have been
proposed to include abnormal excitatory-inhibitory balance in brain regions including the cerebral cortex. The
ATP-dependent chromatin-remodeling factor chromodomain helicase binding protein 8 (CHD8) is one of the
most commonly-mutated genes in sporadic ASD, producing an ASD subtype associated with a high prevalence
of macrocephaly (Barnard et al., Front Neurosci., 2015). In prior work supported by the original grant, we
optimized a human cortical organoid model we developed (Velasco et al., Nature, 2019; Uzquiano et al., Cell,
2022) and applied it to show that CHD8 and other ASD risk genes converge on an early developmental defect
in the GABAergic neuron lineage, leading to asynchronous development of target neurons relative to the other
cell types developing in the organoids (Paulsen et al., Nature, 2022). From this data, we hypothesized that
asynchronous development of GABAergic neurons relative to the excitatory neurons they wire with could lead to
later abnormalities in the activity and function of the cortical local circuit. In support of this hypothesis, we showed
that mutation in another ASD risk gene, SUV420H1, also associated with accelerated development of GABAergic
neurons, leads to abnormal activity of mutant circuits in organoids (Paulsen et al., Nature, 2022). Building on this
data, in this renewal we will leverage our expertise in organoid biology and cortical development together with
co-Investigator Mark Harnett's expertise in human cortical physiology to investigate the effect of heterozygous
loss-of-function of CHD8 on neuronal development and circuit activity using newly-developed organoid models.
Firstly, we will apply a chimeric organoid (“chimeroid”) model (Antón Bolaños and Faravelli et al., preprint at
bioRxiv 2023, and in revision at Nature) to understand whether the genetic context of ASD patients is permissive
for expressivity of the previously-identified CHD8+/- phenotypes (Aim 1). In parallel, we will apply a new human
organoid model of the ventral telencephalon, which we validated to be able to produce GABAergic neurons of
the caudal, medial, and lateral ganglionic eminences (Sartore et al., manuscript in preparation), to understand
whether specific classes of GABAergic interneurons are preferentially affected by CHD8 mutation (Aim 2).
Finally, with the aim of promoting circuits that reflect the endogenous neuronal composition, we will apply a new
“dorsal-ventral chimeroid” organoid model that allows us to control development of the correct proportions of
both excitatory and inhibitory cortical neurons, to investigate cell identity and circuit activity in the CHD8
heterozygous mutant in a more physiologically-relevant system, using calcium imaging, extracellular recording,
and pharmacological manipulations (Aim 3). Taken together, this work will provide mechanistic understanding of
the ro...

## Key facts

- **NIH application ID:** 10980590
- **Project number:** 2R01MH112940-06A1
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Paola Arlotta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $849,543
- **Award type:** 2
- **Project period:** 2018-02-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980590

## Citation

> US National Institutes of Health, RePORTER application 10980590, Modeling ASD-linked genetic mutations in 3D human brain organoids (2R01MH112940-06A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10980590. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*