# Mechanisms of Developmental Anesthesia Toxicity

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $409,375

## Abstract

PROJECT SUMMARY
Epidemiologic studies of human patients have shown a correlation between childhood exposure
to general anesthetic agents and subsequent cognitive deficits. This association is supported
by data from animal models, which shows that developmental exposure to anesthetics causes
lasting impairments in learning. The mechanism by which anesthetic exposure during childhood
could impair subsequent brain function is unknown and no strategies currently exist in clinical
practice to protect patients from the putative risk of anesthetic neurotoxicity. We hypothesize
that developmental exposure to general anesthetics causes a disruption in brain circuit
formation by interfering with dendrite growth and synapse formation, and further that this form of
toxicity is caused by activation of the mTOR pathway, a signaling system associated with
neurodevelopmental disorders. To test this hypothesis we will employ in vivo structural and
functional analysis of mouse and human neurons in the dentate gyrus of the hippocampus. To
address this hypothesis, we will determine the conditions in which commonly used anesthetics
cause pathologic overgrowth of developing dendrites (Aim I); we will determine whether
anesthetics alter the structure and function of synapses on the dendrites of exposed neurons in
vivo (Aim II); finally, we will determine whether anesthetic induced activation of the mTOR
pathway causes a disruption of neuronal circuits and deficits in learning that can be reversed
with a pharmacologic mTOR inhibitor. (Aim III). The proposed studies will not only link pediatric
anesthetic neurotoxicity to a well characterized mechanism of injury that is common to
neurodevelopmental disorders, but it will also explore both a treatment modality, in the form of
the mTOR inhibitor rapamycin, and a prevention strategy, in the form of differential effects
anesthetic choice and dose. The findings will be established in vivo at the single cell level, both
in terms of structure and function, in a well-defined brain circuit in the intact mouse and via the
use using behavioral learning assays that are highly specific for the circuit under study. Key
findings will be verified in human neurons in an in vivo setting, thus establishing relevance to
human biology that is critical for translation. This proposal will explore the broader hypothesis
that pediatric anesthetic neurotoxicity arises from disruptions of brain circuit formation, and more
generally it will contribute to our understanding of neurodevelopmental disorders.

## Key facts

- **NIH application ID:** 9933050
- **Project number:** 5R01GM120519-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Cyrus David Mintz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933050

## Citation

> US National Institutes of Health, RePORTER application 9933050, Mechanisms of Developmental Anesthesia Toxicity (5R01GM120519-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933050. Licensed CC0.

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