Newly Published
Perioperative Medicine  |   April 2018
Ketamine Alters Hippocampal Cell Proliferation and Improves Learning in Mice after Traumatic Brain Injury
Author Notes
  • From the Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon (A.J.P., L.E.V., E.S.)
  • and the Anesthesiology Service, Veterans Affairs Portland Health Care System, Portland, Oregon (E.S.).
  • Part of the work presented in this article has been presented at the following conferences: Society for Neuroscience and Critical Care, October 19, 2017, Boston, Massachusetts; American Society of Anesthesiologists, October 22, 2017, Boston, Massachusetts; Western Anesthesia Residents’ Conference, April 22, 2017, Portland, Oregon (First Place: Best Overall Oral Presentation); Association of University Anesthesiologists, May 5, 2017, Washington, D.C.; and International Anesthesia Research Society, May 7, 2017, Washington, D.C. (Kosaka Best of Meeting Abstract Award Finalist and Top Finalist in Basic Science Research).
    Part of the work presented in this article has been presented at the following conferences: Society for Neuroscience and Critical Care, October 19, 2017, Boston, Massachusetts; American Society of Anesthesiologists, October 22, 2017, Boston, Massachusetts; Western Anesthesia Residents’ Conference, April 22, 2017, Portland, Oregon (First Place: Best Overall Oral Presentation); Association of University Anesthesiologists, May 5, 2017, Washington, D.C.; and International Anesthesia Research Society, May 7, 2017, Washington, D.C. (Kosaka Best of Meeting Abstract Award Finalist and Top Finalist in Basic Science Research).×
  • Submitted for publication October 13, 2017. Accepted for publication February 28, 2018.
    Submitted for publication October 13, 2017. Accepted for publication February 28, 2018.×
  • Acknowledgments: The authors would like to thank the following: Gary Westbrook, M.D., senior scientist at the Vollum Institute, Portland, Oregon, for project guidance; members of the Westbrook and Schnell labs, Portland, Oregon, for helpful discussions; David Yanez, Ph.D., associate professor of biostatistics and codirector of the Biostatistics and Design Program, Oregon Health and Science University, Portland, Oregon, for statistical guidance and interpretation; and Sarah Mader, B.S., research assistant, Department of Anesthesiology, Oregon Health and Science University, for outstanding technical support. The contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs or the United States government.
    Acknowledgments: The authors would like to thank the following: Gary Westbrook, M.D., senior scientist at the Vollum Institute, Portland, Oregon, for project guidance; members of the Westbrook and Schnell labs, Portland, Oregon, for helpful discussions; David Yanez, Ph.D., associate professor of biostatistics and codirector of the Biostatistics and Design Program, Oregon Health and Science University, Portland, Oregon, for statistical guidance and interpretation; and Sarah Mader, B.S., research assistant, Department of Anesthesiology, Oregon Health and Science University, for outstanding technical support. The contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs or the United States government.×
  • Research Support: Primary funding for this project was provided by a Foundation for Anesthesia Education and Research (Schaumburg, Illinois) Research Fellowship Grant (to Dr. Peters). Additional funding was provided by a BIRCWH K12 award made possible through the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Bethesda, Maryland) and the Office of Research on Women’s Health (Bethesda, Maryland; grant No. K12 HD 043488; to Dr. Villasana), a Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (Washington, D.C.), Biomedical Laboratory Research and Development (Washington, D.C.) CDA-2 Award 005-10S (to Dr. Schnell), a Department of Veterans Affairs Merit Review Award I01-BX002949 (to Dr. Schnell), and Oregon Health and Science University (Portland, Oregon) Anesthesiology and Perioperative Medicine departmental funds. Supplementary equipment and developmental funds were provided by the Oregon Clinical and Translational Research Institute (Portland, Oregon) grant No. TL1TR000129 and National Institute for Neurological Disorders and Stroke (Bethesda, Maryland) grant No. P30 NS061800.
    Research Support: Primary funding for this project was provided by a Foundation for Anesthesia Education and Research (Schaumburg, Illinois) Research Fellowship Grant (to Dr. Peters). Additional funding was provided by a BIRCWH K12 award made possible through the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Bethesda, Maryland) and the Office of Research on Women’s Health (Bethesda, Maryland; grant No. K12 HD 043488; to Dr. Villasana), a Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (Washington, D.C.), Biomedical Laboratory Research and Development (Washington, D.C.) CDA-2 Award 005-10S (to Dr. Schnell), a Department of Veterans Affairs Merit Review Award I01-BX002949 (to Dr. Schnell), and Oregon Health and Science University (Portland, Oregon) Anesthesiology and Perioperative Medicine departmental funds. Supplementary equipment and developmental funds were provided by the Oregon Clinical and Translational Research Institute (Portland, Oregon) grant No. TL1TR000129 and National Institute for Neurological Disorders and Stroke (Bethesda, Maryland) grant No. P30 NS061800.×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Schnell: VA Portland Health Care System, 3170 SW US Veterans Hospital Road, P3ANES, Portland, Oregon 97239. schneler@ohsu.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Central and Peripheral Nervous Systems / Pharmacology
Perioperative Medicine   |   April 2018
Ketamine Alters Hippocampal Cell Proliferation and Improves Learning in Mice after Traumatic Brain Injury
Anesthesiology Newly Published on April 30, 2018. doi:10.1097/ALN.0000000000002197
Anesthesiology Newly Published on April 30, 2018. doi:10.1097/ALN.0000000000002197
Abstract

Background: Traumatic brain injury induces cellular proliferation in the hippocampus, which generates new neurons and glial cells during recovery. This process is regulated by N-methyl-d-aspartate–type glutamate receptors, which are inhibited by ketamine. The authors hypothesized that ketamine treatment after traumatic brain injury would reduce hippocampal cell proliferation, leading to worse behavioral outcomes in mice.

Methods: Traumatic brain injury was induced in mice using a controlled cortical impact injury, after which mice (N = 118) received either ketamine or vehicle systemically for 1 week. The authors utilized immunohistochemical assays to evaluate neuronal, astroglial, and microglial cell proliferation and survival 3 days, 2 weeks, and 6 weeks postintervention. The Morris water maze reversal task was used to assess cognitive recovery.

Results: Ketamine dramatically increased microglial proliferation in the granule cell layer of the hippocampus 3 days after injury (injury + vehicle, 2,800 ± 2,700 cells/mm3, n = 4; injury + ketamine, 11,200 ± 6,600 cells/mm3, n = 6; P = 0.012). Ketamine treatment also prevented the production of astrocytes 2 weeks after injury (sham + vehicle, 2,400 ± 3,200 cells/mm3, n = 13; injury + vehicle, 10,500 ± 11,300 cells/mm3, n = 12; P = 0.013 vs. sham + vehicle; sham + ketamine, 3,500 ± 4,900 cells/mm3, n = 14; injury + ketamine, 4,800 ± 3,000 cells/mm3, n = 13; P = 0.955 vs. sham + ketamine). Independent of injury, ketamine temporarily reduced neurogenesis (vehicle-exposed, 105,100 ± 66,700, cells/mm3, n = 25; ketamine-exposed, 74,300 ± 29,200 cells/mm3, n = 27; P = 0.031). Ketamine administration improved performance in the Morris water maze reversal test after injury, but had no effect on performance in sham-treated mice.

Conclusions: Ketamine alters hippocampal cell proliferation after traumatic brain injury. Surprisingly, these changes were associated with improvement in a neurogenesis-related behavioral recall task, suggesting a possible benefit from ketamine administration after traumatic brain injury in mice. Future studies are needed to determine generalizability and mechanism.