# Astrocyte dysfunction in idiopathic autism

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $419,083

## Abstract

PROJECT SUMMARY
Autism Spectrum Disorder (ASD) is a developmental disease that refers to a broad range of conditions
characterized by challenges with sociability, repetitive behaviors, communication as well as cognitive deficits.
Although the exact molecular mechanisms of ASD are poorly understood, cumulative evidence suggests that
abnormal synapse development underlies many features of this disease. Most work in the field has focused on
neuronal abnormalities while glial pathology in ASD has been overlooked for decades. A large number of
autism-linked genes are highly expressed and significantly enriched in astrocytes suggesting a role for
astrocyte dysfunction in the synaptic abnormalities observed in ASD.
Astrocytes have been implicated in the pathogenesis of mouse models of syndromic ASDs. However, a
detailed characterization of astrocyte dysfunction in ASD has not been completed, and it therefore remains
unclear whether astrocyte dysfunction directly contributes to the synaptic plasticity and behavioral outcomes of
ASD. Approximately 95 percent of ASD are idiopathic cases where autism is the primary diagnosis and not
secondary to an existing condition caused by a well-known genetic variant. Human postmortem studies
suggest that astrogliosis is one of the molecular features of ASD. However, it remains unclear whether
astrocyte pathology plays a causative role in ASD, as opposed to representing a compensatory mechanism.
The goal of this application is to understand the role of astrocyte dysfunction in idiopathic ASD. We have found
that!mice exhibit social and memory deficits following neonatal brain engraftment of neural progenitors derived
from ASD patient induced pluripotent stem cells. These progenitors terminally differentiated into astrocytes in
transplanted brains, indicating that astrocytes account for the behavioral phenotypes observed in the ASD
chimeric mice. Similarly, mice engrafted with astrocytes isolated from patient cerebral organoids exhibited
reduced sociability. Based on the published literature and our preliminary studies, we hypothesize that
astrocyte dysfunction is an underlying mechanism in ASD and contributes to specific behavioral impairments in
this disorder. To test this hypothesis, we propose to determine 1) the behavioral impairments that astrocytes
contribute to in ASD; 2) the functional deficits of ASD astrocytes (e.g., by assessing Ca2+ activity, protein profile
and neurotransmitter uptake ability); and 3) the effects of ASD astrocytes on neurons (e.g., assessing neuronal
network connectivity and synaptic plasticity). We will use a combination of techniques including patient-derived
cerebral organoids, cell transplantation, two-photon Ca2+ imaging, electrophysiology and behavioral assays.
Despite the growing realization of the importance of astrocytes in synaptic function and connectivity, astrocyte
dysfunction represents a relatively unexplored mechanism for the onset and progression of ASD. The
successful comp...

## Key facts

- **NIH application ID:** 9968448
- **Project number:** 5R01MH120156-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Dilek Colak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,083
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968448

## Citation

> US National Institutes of Health, RePORTER application 9968448, Astrocyte dysfunction in idiopathic autism (5R01MH120156-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9968448. Licensed CC0.

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