Anesthetics interfere with axon guidance in developing mouse neocortical neurons in vitro via a γ-aminobutyric acid type a receptor mechanism

Cyrus David Mintz, Kendall M S Barrett, Sarah C. Smith, Deanna L. Benson, Neil L. Harrison

Research output: Contribution to journalArticle

Abstract

Background: The finding that exposure to general anesthetics (GAs) in childhood may increase rates of learning disabilities has raised a concern that anesthetics may interfere with brain development. The generation of neuronal circuits, a complex process in which axons follow guidance cues to dendritic targets, is an unexplored potential target for this type of toxicity. Methods: GA exposures were conducted in developing neocortical neurons in culture and in early postnatal neocortical slices overlaid with fluorescently labeled neurons. Axon targeting, growth cone collapse, and axon branching were measured using quantitative fluorescence microscopy. Results: Isoflurane exposure causes errors in Semaphorin-3A-dependent axon targeting (n = 77 axons) and a disruption of the response of axonal growth cones to Semaphorin-3A (n = 2,358 growth cones). This effect occurs at clinically relevant anesthetic doses of numerous GAs with allosteric activity at γ-aminobutyric acid type A receptors, and it was reproduced with a selective agonist. Isoflurane also inhibits growth cone collapse induced by Netrin-1, but does not interfere branch induction by Netrin-1. Insensitivity to guidance cues caused by isoflurane is seen acutely in growth cones in dissociated culture, and errors in axon targeting in brain slice culture occur at the earliest point at which correct targeting is observed in controls. Conclusions: These results demonstrate a generalized inhibitory effect of GAs on repulsive growth cone guidance in the developing neocortex that may occur via a γ-aminobutyric acid type A receptor mechanism. The finding that GAs interfere with axon guidance, and thus potentially with circuit formation, represents a novel form of anesthesia neurotoxicity in brain development.

Original languageEnglish (US)
Pages (from-to)825-833
Number of pages9
JournalAnesthesiology
Volume118
Issue number4
DOIs
StatePublished - Apr 2013
Externally publishedYes

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Aminobutyrates
Growth Cones
General Anesthetics
Anesthetics
Axons
Neurons
Isoflurane
Semaphorin-3A
Cues
Brain
Learning Disorders
Neocortex
Fluorescence Microscopy
Axon Guidance
In Vitro Techniques
Anesthesia

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Anesthetics interfere with axon guidance in developing mouse neocortical neurons in vitro via a γ-aminobutyric acid type a receptor mechanism. / Mintz, Cyrus David; Barrett, Kendall M S; Smith, Sarah C.; Benson, Deanna L.; Harrison, Neil L.

In: Anesthesiology, Vol. 118, No. 4, 04.2013, p. 825-833.

Research output: Contribution to journalArticle

Mintz, Cyrus David ; Barrett, Kendall M S ; Smith, Sarah C. ; Benson, Deanna L. ; Harrison, Neil L. / Anesthetics interfere with axon guidance in developing mouse neocortical neurons in vitro via a γ-aminobutyric acid type a receptor mechanism. In: Anesthesiology. 2013 ; Vol. 118, No. 4. pp. 825-833.
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