# Serotonergic modulation of excitatory synapse formation and maturation during development

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $383,700

## Abstract

Project Summary
Autism Spectrum Disorders (ASDs) comprise a group of severe neurodevelopmental disorders that are typified
by communication deficits and social impairment. Given that the onset of symptoms occurs by the age of 3, it is
largely agreed that neuronal dysfunction arises during early brain development. A developing brain shows a
remarkable capacity for plastic changes in response to experiences; thus, its development is most vulnerable to
the environmental factors that can derail normal brain function. In utero exposure to drugs that raise blood 5HT
levels, including selective serotonin reuptake inhibitors (SSRIs), has demonstrated behavioral and psychological
deficits in offspring that closely resemble autistic symptoms in both animals models and human studies. In order
to understand how these alterations arise, it is necessary to first understand the basic mechanisms of
serotonergic modulation of brain function. Formation and stabilization of excitatory synapses are known to be
essential for the initial establishment of functional neural circuits. Conversely, disrupted synapse development
impairs neuron function and is thought to underlie the pathology of multiple neurodevelopmental disorders. PFC
is densely innervated by serotonergic axon terminals and associated with higher cognitive processes that may
be disrupted in illnesses such as ASDs. Despite a wealth of literature examining the role of 5HT in modulating
behavior and in the pathogenesis of brain disorders, little is known at the cellular and molecular level about the
role of 5HT in early cortical development, and particularly the postsynaptic 5HT mechanisms that modulate
synapse development in the developing PFC. In the present study, we utilize a novel combination of tools
including two-color, two-photon uncaging that enables precise release of 5HT and glutamate neurotransmitters,
calcium imaging, electrophysiology, and optogenetic stimulation of genetically-targeted 5HT neurons to test our
central hypothesis that 5HT signaling promotes the initiation of excitatory synapse formation and controls the
maturation of excitatory synapses during brain development. Guided by strong preliminary data, we will examine
this hypothesis in two specific aims: 1) Determine the role of 5HT signaling in lowering the threshold for induction
of activity-dependent synapse formation. 2) Define the actions of 5HT on activity-dependent, input-specific and
heterosynaptic spine stabilization. Results from these studies will further our understanding of the unique and
detailed mechanisms by which 5HT regulates brain development, with critical relevance to cellular underpinnings
of neurodevelopmental disorders. In the U.S., approximately 13% of pregnant women use SSRIs, which typically
increase fetal 5HT levels. We expect that our results will highlight new avenues into the investigation of the
pathophysiology underlying neurodevelopmental disorders resulting from early perturbation of 5HT signaling.

## Key facts

- **NIH application ID:** 10096510
- **Project number:** 1R01MH124778-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Won Chan Oh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $383,700
- **Award type:** 1
- **Project period:** 2020-12-01 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10096510

## Citation

> US National Institutes of Health, RePORTER application 10096510, Serotonergic modulation of excitatory synapse formation and maturation during development (1R01MH124778-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10096510. Licensed CC0.

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