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Early Exposure to Ketamine Impairs Axonal Pruning in Developing Mouse Hippocampus

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Abstract

Mounting evidence suggests that prolonged exposure to general anesthesia (GA) during brain synaptogenesis damages the immature neurons and results in long-term neurocognitive impairments. Importantly, synaptogenesis relies on timely axon pruning to select axons that participate in active neural circuit formation. This process is in part dependent on proper homeostasis of neurotrophic factors, in particular brain-derived neurotrophic factor (BDNF). We set out to examine how GA may modulate axon maintenance and pruning and focused on the role of BDNF. We exposed post-natal day (PND)7 mice to ketamine using a well-established dosing regimen known to induce significant developmental neurotoxicity. We performed morphometric analyses of the infrapyramidal bundle (IPB) since IPB is known to undergo intense developmental modeling and as such is commonly used as a well-established model of in vivo pruning in rodents. When IPB remodeling was followed from PND10 until PND65, we noted a delay in axonal pruning in ketamine-treated animals when compared to controls; this impairment coincided with ketamine-induced downregulation in BDNF protein expression and maturation suggesting two conclusions: a surge in BDNF protein expression “signals” intense IPB pruning in control animals and ketamine-induced downregulation of BDNF synthesis and maturation could contribute to impaired IPB pruning. We conclude that the combined effects on BDNF homeostasis and impaired axon pruning may in part explain ketamine-induced impairment of neuronal circuitry formation.

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Acknowledgments

This study was supported by the grants R0144517 (NIH/NICHD), R0144517-S (NIH/NICHD), R01 GM118197 (NIH/NIGMS), R21 HD080281 (NIH/NICHD), John E. Fogarty Award 007423-128322 (NIH), and March of Dimes National Award, USA (to Vesna Jevtovic-Todorovic). Vesna Jevtovic-Todorovic was an Established Investigator of the American Heart Association. We thank Jonathan Park for his assistance with the morphometric analysis of the IPB pruning.

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Authors and Affiliations

  1. Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA

    Aleksandar Lj. Obradovic

  2. Department of Anesthesiology, University of Colorado School of Medicine, 12401 East 17th Avenue, Aurora, CO, 80045, USA

    Navya Atluri, Hari P. Osuru & Vesna Jevtovic-Todorovic

  3. Department of Anesthesiology and Pharmacology, University of Padua, Padua, Italy

    Lorenza Dalla Massara

  4. Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA

    Azra Oklopcic

  5. University of Virginia College of Arts and Sciences, Charlottesville, VA, USA

    Nikola S. Todorovic

  6. Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA

    Gaurav Katta

Authors
  1. Aleksandar Lj. Obradovic
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  2. Navya Atluri
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  3. Lorenza Dalla Massara
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  4. Azra Oklopcic
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  5. Nikola S. Todorovic
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  6. Gaurav Katta
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  7. Hari P. Osuru
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  8. Vesna Jevtovic-Todorovic
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Corresponding author

Correspondence to Vesna Jevtovic-Todorovic.

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The authors declare that they have no competing interests.

Human and Animal Rights and Informed Consent

The experiments were approved by the Animal Use and Care Committees at the University of Colorado, the Office of Laboratory Animal Resources (OLAR), Aurora, Colorado and the Animal Use and Care Committees of the University of Virginia, Charlottesville, Virginia. The experiments were done in accordance with the Public Health Service’s Policy on Humane Care and Use of Laboratory Animals.

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Obradovic, A.L., Atluri, N., Dalla Massara, L. et al. Early Exposure to Ketamine Impairs Axonal Pruning in Developing Mouse Hippocampus. Mol Neurobiol 55, 164–172 (2018). https://doi.org/10.1007/s12035-017-0730-0

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  • DOI: https://doi.org/10.1007/s12035-017-0730-0

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