# Mechanisms of synaptic and behavioral dysfunction after postnatal anesthesia

> **NIH NIH K08** · UNIVERSITY OF VIRGINIA · 2020 · $189,104

## Abstract

Over 4 million infants and young children undergo general anesthesia (GA) every year in the US. Experimental
evidence suggests that several mammalian species may suffer neurodegeneration, followed by long-lasting
cognitive impairment, when exposed to common intravenous and inhaled anesthetics during critical stages of
brain development. Recent studies also document disruption of sleep-wake behavior following GA with volatile
anesthetics. To date, the mechanisms underlying the behavioral dysfunctions observed after GA remain
incompletely understood and the effects of an early anesthetic exposure on synaptic function have not been
explored in detail. Thus, the long term objectives of this proposal are to establish how exposure to GA alters
synaptic plasticity, synaptic networking and behavioral output in the developing hippocampus and to decipher
the mechanisms of GA-induced synaptic dysregulation. We address the specific hypothesis that a key
component of the neurotransmitter release machinery, synapsin I, features decisively in the pathophysiology of
GA-induced synaptic and cognitive dysfunction. This project encompasses three specific aims. In Specific
Aim 1, we test the molecular effects of GA on the expression of pre-synaptic neurotransmitter release
machinery components. This is achieved by western blot and qPCR quantification of several key components
of the machine for vesicle release. In Specific Aim 2, we test the cellular effects of GA-induced impairment of
the release machinery on synaptic transmission and plasticity. This is achieved by systematic
electrophysiology experiments of basal synaptic transmission, plasticity, excitability and networking. In
Specific Aim 3, we test the effects of anesthetics on learning, memory and sleep-wake behavior, using the
Barnes maze, fear conditioning test and quantitative electroencephalographic analysis of sleep-wake patterns.
Collectively, the proposed studies will provide new understanding of the molecular and cellular mechanisms of
GA-induced synaptic dysregulation and behavioral dysfunction, and the rationale for new therapeutic strategies
to prevent or improve cognitive, sleep-wake and other behavioral developmental dysfunctions after GA
exposure. As a result of my training and research experience, I have the expertise necessary to successfully
carry out this work. I assembled a cadre of senior investigators who are participating enthusiastically in my
mentoring and my Chair has committed to me the protected time, all of the facilities and equipment that are
needed to develop into a successful translational research scientist. My short term objective is to use this
Award to acquire new skills to pursue my own niche of research, focusing on the role of sleep in anesthesia-
induced cognitive dysfunction in the young and aging brain, and on the role of the synaptic fusion mechanism
in neurological disorders and imbalances of neurotransmission. My long-term career objective is to become an
independ...

## Key facts

- **NIH application ID:** 9983115
- **Project number:** 5K08GM123321-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Nadia Lunardi
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $189,104
- **Award type:** 5
- **Project period:** 2017-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983115

## Citation

> US National Institutes of Health, RePORTER application 9983115, Mechanisms of synaptic and behavioral dysfunction after postnatal anesthesia (5K08GM123321-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9983115. Licensed CC0.

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