Ketamine Alters Hippocampal Cell Proliferation and Improves Learning in Mice after Traumatic Brain Injury

Austin J. Peters, Laura Villasana, Eric Schnell

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1278-1295
Number of pages18
JournalAnesthesiology
Volume129
Issue number2
DOIs
StatePublished - Aug 1 2018

Fingerprint

Ketamine
Cell Proliferation
Learning
Wounds and Injuries
Neurogenesis
Traumatic Brain Injury
Hippocampus
Water
Glutamate Receptors
N-Methyl-D-Aspartate Receptors
Neuroglia
Astrocytes
Cell Survival

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Ketamine Alters Hippocampal Cell Proliferation and Improves Learning in Mice after Traumatic Brain Injury. / Peters, Austin J.; Villasana, Laura; Schnell, Eric.

In: Anesthesiology, Vol. 129, No. 2, 01.08.2018, p. 1278-1295.

Research output: Contribution to journalArticle

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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.",
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N2 - 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.

AB - 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.

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