# Antiretroviral Drug-Induced Changes in Synapses between Human iPSC-Derived Cortical Neurons to Assess Risk and Mechanisms of Neuropsychiatric Adverse Effects

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2020 · $192,500

## Abstract

Summary: Antiretroviral Drug-Induced Changes in Synapses between Human iPSC-Derived Cortical Neurons
to Assess Risk and Mechanisms of Neuropsychiatric Adverse Effects
Combined antiretroviral therapy (cART) has dramatically increased the survival and improved the quality of life
for HIV-1 infected patients. There is growing concern that while cART decreases HIV-1 neurotoxicity by
reducing viral load, antiretroviral drugs themselves may produce neurotoxicity. In some patients, antiretroviral
drugs elicit symptoms of depression and anxiety. These symptoms, like many neuropsychiatric disorders may
be associated with a reduction in the number of synaptic contacts. We developed a high content imaging
approach to quantify functional glutamatergic synapses between neurons in culture. This highly automated
high content analysis (HCA) assay is exquisitely sensitive to agents that reduce dendritic spine density
between rat neurons in primary culture. In this proposal, we describe the modification of this assay to assess
synaptic contacts between human induced pluripotent stem cell (hiPSC)–derived cortical neurons. The use of
human neurons is warranted because human synapses are uniquely sensitive to some neurotoxic insults. We
will use this assay to evaluate the synaptic toxicity of antiretroviral drugs alone and in the presence of synaptic
modifiers associated with risk of psychiatric disease. Three specific aims are proposed. In aim 1, we will
optimize the HCA assay for detecting synapses between hiPSC-derived neurons. An automated assay to
quantify synaptic connections between live human neurons will have broad application for studying the
mechanism of synaptic changes that underlie psychiatric disorders. In aim 2, we will determine whether
antiretroviral drugs are toxic to synapses between hiPSC-derived cortical neurons. These results will identify
antiretroviral drugs with a particular propensity to impair synaptic function. In aim 3, we will evaluate synaptic
modifiers for altered risk of antiretroviral-induced synaptic toxicity. A limited screen in the presence of
increased pro-inflammatory cytokines, elevated stress hormones, or reduced levels of neurotrophic factors
alone and in combination with antiretroviral drugs will be performed to determine potential synergistic effects.
These studies will establish a proof of concept for using the HCA assay to identify risk factors that potentiate
antiretroviral drug-induced loss of synapses between human cortical neurons. The results from this project will
determine the feasibility of using an HCA assay to identify synaptic changes with the potential to produce
neuropsychiatric side effects and will provide a foundation for future studies to probe the mechanism and
potential reversal of synapse loss. Identification of combinations of antiretroviral drugs and risk factors that
produce synapse loss could inform the clinical care of persons living with HIV. Finally, with further validation
this assay may assis...

## Key facts

- **NIH application ID:** 10023282
- **Project number:** 5R21MH122193-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Stanley A Thayer
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $192,500
- **Award type:** 5
- **Project period:** 2019-09-24 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023282

## Citation

> US National Institutes of Health, RePORTER application 10023282, Antiretroviral Drug-Induced Changes in Synapses between Human iPSC-Derived Cortical Neurons to Assess Risk and Mechanisms of Neuropsychiatric Adverse Effects (5R21MH122193-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10023282. Licensed CC0.

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