# Human Embryonic Stem Cell Models for Studying Mechanisms Underlying Changes In Inhibitory Synapses in Down Syndrome

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $429,000

## Abstract

ABSTRACT:
Down syndrome (DS), the chromosomal disorder caused by trisomy of chromosome 21 (Tri21), presents many
neurological conditions, including intellectual disability (ID), autism spectrum disorder (ASD), epilepsy, and
Alzheimer’s disease (AD), and is the most common genetic cause of intellectual disability worldwide. Although
some human chromosome 21 (HSA21) genes have been identified as key contributors to some of these
pathologies, the mechanisms that link the triplication of HSA21 genes to most DS-related diseases remain
largely unknown. Many DS-related neurological conditions are caused by a dysregulated GABAergic system.
Excessive GABAergic functions impair synaptic plasticity and memory formation in DS mouse models. DS
mouse models exhibit synaptic plasticity deficits, which are rescued by GABA receptor antagonists. Our
primary goal is to discover the molecular underpinnings that cause human GABAergic dysregulation, which
will provide critical knowledge for understanding the pathogenesis of DS-related human brain disorders, and
for developing effective human treatments. Down syndrome cell adhesion molecule (DSCAM) is a major cause
of the increased GABAergic synapses and enhanced GABAergic synaptic transmission in the neocortex of DS
mouse models. Normalization of DSCAM dosage rescued the excessive GABAergic innervation on pyramidal
neuron soma and axon initial segments and prevented the increase in postsynaptic inhibitory current
frequency. DSCAM is expressed in GABAergic neurons as well as other neuronal types and is overexpressed
in the brains of DS patients and DS mouse models. Human genetics studies have shown strong associations
between DSCAM variants and cognitive abilities. These findings raise the possibility that DSCAM
overexpression might explain the dysregulation of GABAergic synapses in DS. However, whether the HSA21
dosage and overexpression of DSCAM is causative of GABAergic neuron dysfunction in humans remains to be
studied. We hypothesize that DSCAM triplication, resulting from trisomy 21, causes dysregulated
GABAergic interneuron development and synaptogenesis in human trisomy 21 cell models. To test this
hypothesis, we will use GABAergic neurons derived from control and trisomy 21 human embryonic stem cells.
The combined expertise of the Smith and Ye labs is ideally suited for the proposed study. The proposed study
is significant because its successful accomplishment will identify the molecular regulators of the GABAergic
system in human neurons. This knowledge will offer insights into the development of therapeutic treatments
that target DS-related conditions that are caused by dysregulated GABAergic synapses. It will also provide
molecular and cellular insights into many neurological disorders, such as other intellectual disabilities, epilepsy,
ASD, and neurodegenerative disorders such as AD.
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## Key facts

- **NIH application ID:** 10950411
- **Project number:** 1R21HD116010-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** GARY DANIEL SMITH
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $429,000
- **Award type:** 1
- **Project period:** 2024-09-11 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10950411

## Citation

> US National Institutes of Health, RePORTER application 10950411, Human Embryonic Stem Cell Models for Studying Mechanisms Underlying Changes In Inhibitory Synapses in Down Syndrome (1R21HD116010-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10950411. Licensed CC0.

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