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

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What We Already Know about This TopicAn important response of the injured brain is an increase in glial proliferation and, in particular, neurogenesis in the hippocampus. This neurogenesis, which is dependent upon N-methyl-D-aspartate receptors, is of significant benefit in the normal brain.Ketamine is an anesthetic agent that is employed for sedation in head-injured patients. Given that ketamine is an N-methyl-D-aspartate receptor antagonist, it is possible that it might adversely impact injury-induced neurogenesis.What This Article Tells Us That Is NewIn mice subjected to traumatic brain injury, ketamine significantly increased hippocampal cell proliferation. Surprisingly, the increased proliferation was largely a product of increased microgliogenesis. Ketamine administration also improved behavioral function after injury.The demonstration that ketamine administration modulates the brain response after head injury suggests that ketamine may, at least in experimental models, also alter long-term behavioral outcomes.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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