# Gene expression profiling of IPSC derived neurons in Autism Spectrum Disorder

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $737,332

## Abstract

Autism Spectrum Disorder (ASD) is a genetically and phenotypically heterogeneous
neurodevelopmental disorder. Hundreds of genes contribute to the risk to develop ASD with no individual
genetic locus accounting for more than 1% of cases. This raises the issue of whether, and how such diverse
mechanisms converge on a smaller number of biological pathways that ultimately result in one phenotype,
namely ASD. The inability to study neurons and brains from living subjects has blocked progress toward
understanding the cellular and molecular mechanisms underlying ASD and other neurodevelopmental
disorders.
Neurons derived from human induced pluripotent stem cell (hiPSC) recapitulate multiple stages of in
vivo neural development in vitro. Because they retain the genetic makeup of the patient they enable in vitro
studies of neurons that harbor the complex genetic background associated with ASD. Deriving neurons from
hiPSCs is labor intensive and costly, and to date studies have examined very small numbers of patients.
hiPSC studies of the scope required to capture idiopathic ASD have not been possible, entirely limiting our
ability to determine the mechanistic underpinnings of this form of the disorder. We propose to conduct an
investigation of hiPSC derived neurons on an unprecedented scale by leveraging our California Institute for
Regenerative Medicine (CIRM) funded existing collection of over 300 hiPSCs, to examine 100 individuals with
idiopathic ASD and 100 age- and sex-matched controls. We will use commercially derived neurons (iCell
Neurons) which are a >95% pure population of glutamatergic (excitatory) and GABAergic (inhibitory) neurons.
To identify dysregulated molecular pathways in these neurons we will sequence the human transcriptome at
three time points during maturation of the neurons. We will also conduct assays of cell viability, morphology,
neurite outgrowth using live cell imaging, and function through calcium imaging. We aim to identify
dysregulated molecular pathways in these hiPSC-derived neurons from individuals with ASD, by identifying
genes that are differentially expressed from controls at each time point and perform a factorial analysis to study
interactive effects between time point and disease variable. This will identify genes showing differentiation-
induced expression changes across neuronal differentiation in individuals with ASD. We will identify key
drivers of biological pathway changes using Weighted Gene Co-expression Network Analysis (WGCNA).
Finally, we will relate gene expression profiles to cellular and behavioral phenotypes.

## Key facts

- **NIH application ID:** 10320346
- **Project number:** 5R01MH116674-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** JOACHIM F HALLMAYER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $737,332
- **Award type:** 5
- **Project period:** 2018-04-06 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320346

## Citation

> US National Institutes of Health, RePORTER application 10320346, Gene expression profiling of IPSC derived neurons in Autism Spectrum Disorder (5R01MH116674-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10320346. Licensed CC0.

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