# Project 3 Arlotta

> **NIH NIH P50** · HARVARD UNIVERSITY · 2021 · $490,100

## Abstract

Modeling ASD-linked mutations in 3D human brain organoids
 Neuropsychiatric diseases are very complex, and we still have a limited
understanding of the abnormalities associated with genetic mutation in these pathologies.
This is in part complicated by the lack of single, ideal experimental models for these
overtly “human” diseases, and the need to investigate abnormalities in diverse genetic
backgrounds. Rodent models have proven valuable to highlight phenotypic abnormalities
associated with autism spectrum disorder (ASD)-linked mutations. However, rodents
differ in the development, architecture and function of their brain compared to humans
making discoveries difficult to relate to patients. We share the vision of this consortium
that integrated investigation of multiple experimental models, including models of the
human brain, is needed to progress understanding of ASD. Studies using human brain
tissue are complicated by practical and ethical concerns of tissue availability, expansion
and manipulation. However, recent progress has enabled the development of cellular
models of the human developing brain via the generation of 3D brain organoids, which
we propose can complement rodent and non-human primate systems to model basic
aspects of human pathology. Although reductionist in nature, 3D brain organoids are
amenable to high-throughput genetic engineering and can provide a valuable platform to
link mutations in disease-associated genes with specific abnormalities in human
neurons and circuits, as well as help identify molecular targets. Here, we will use a
protocol that we recently established to generate long-term cultures of human brain
organoids engineered to carry the same mutations in the SHANK3 and MECP2 genes
investigated in rodents and marmosets by the other members of the consortium. We will
pioneer extensive molecular, morphological and electrophysiological analysis of mutant
and control organoids to understand whether these mutations induce defects in human
neurons and networks similar to those observed in mice, and to generate a
transcriptional map of molecular changes that informs mechanistic understanding. In
addition, we will optimize our recent Method for Analyzing RNA following Intracellular
Sorting (MARIS) to molecularly profile specific subclasses of cortical neurons from
rodent and marmoset brain and brain organoids. This will provide the first inter-species
comparison of disease-relevant mutant and control neurons in three model systems to
highlight molecular abnormalities and pinpoint cell type-specific defects.

## Key facts

- **NIH application ID:** 10145783
- **Project number:** 5P50MH094271-09
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Paola Arlotta
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $490,100
- **Award type:** 5
- **Project period:** 2011-09-05 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145783

## Citation

> US National Institutes of Health, RePORTER application 10145783, Project 3 Arlotta (5P50MH094271-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145783. Licensed CC0.

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