# lncRNAs and Anesthetic-Induced Developmental Neurotoxicity

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $327,250

## Abstract

PROJECT SUMMARY: In 2016, the U.S. Food and Drug Administration warned that repeated or lengthy use
of general anesthetics in children below the age of three might affect their brain development. This warning
raises serious concerns regarding the safety of pediatric anesthesia. There are two main barriers in the
research field of anesthetic-induced developmental neurotoxicity (AIDN): 1) So far, most of the evidence for
AIDN was obtained from animal studies. The results from human studies remain inconclusive. 2) The
mechanisms are largely unknown. The goal of this proposed study is to address both of these barriers. First,
we established a new in vitro system of three-dimensional (3D) human mini brains using induced pluripotent
stem cells for modeling human brain development. Human mini brains are more similar to developing human
brains, both structurally and functionally, than the widely used 2D neurons. Thus, application of human mini
brains in AIDN research field helps bridge the gap between the animal and human studies. Our preliminary
data provided the first evidence showing that clinically relevant doses of either propofol or sevoflurane, two
commonly used pediatric anesthetics, induced cell death in human mini brains. Second, we recently used an
unbiased approach to screen the expression of 24,881 long non-coding RNAs (lncRNAs) and 35,923
messenger RNAs in neonatal mouse hippocampi. We discovered that the expression levels of the lncRNA
AK156531 gene, and its nearby protein-coding gene Neuronal Per Arnt Sim domain protein 4 (NPAS4), were
dramatically decreased following propofol exposure. One of the known functions of lncRNAs is to regulate their
nearby gene expression. We found that knockdown of AK156531 decreased NPAS4 levels in both human mini
brains and mouse brains, strongly suggesting that AK156531 might regulate NPAS4 expression. NPAS4 is
involved in excitatory/inhibitory (E/I) balance, learning and memory, and neuroprotection. We also found that
neonatal propofol exposure caused multiple adverse effects in mice (E/I imbalance, neuronal death, and
impaired memory function). These exciting findings, combined with the reported function of NPAS4, suggest
that the abnormally expressed AK156531 might directly contribute to AIDN. Thus, we propose to utilize
AK156531 gain- and loss-of-function approaches to examine the role and mechanism of AK156531 in AIDN in
mice, and to facilitate the translation of these findings to humans by using human mini brains. We hypothesize
that downregulation of AK156531 contributes to E/I imbalance, neuronal death and cognitive dysfunction via
NPAS4 signaling. For the first time in this field, human mini brains will be combined with AK156531 knockdown
and overexpression mouse models to investigate the novel mechanisms of lncRNA involvement. This proposal
is expected to provide new mechanistic insights into the neurodevelopmental consequences of pediatric
anesthetic exposure. This will further aid in the develo...

## Key facts

- **NIH application ID:** 9980423
- **Project number:** 5R01GM112696-07
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Xiaowen Bai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $327,250
- **Award type:** 5
- **Project period:** 2014-05-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980423

## Citation

> US National Institutes of Health, RePORTER application 9980423, lncRNAs and Anesthetic-Induced Developmental Neurotoxicity (5R01GM112696-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980423. Licensed CC0.

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