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

Abstract

What We Already Know about This Topic What This Article Tells Us That Is New 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.

Mild Traumatic Brain Injury Induces Transient, Sequential Increases in Proliferation, Neuroblasts/Immature Neurons, and Cell Survival: A Time Course Study in the Male Mouse Dentate Gyrus

“…Therefore, examination of neurogenesis indices 3 dpi may reveal changes that influence the subsequent emergence of 7 dpi DG hyperexcitability and functional impairment. Second, indices of DG proliferation and neurogenesis are changed 3 dpi in more severe TBI models relative to control animals ( Dash et al, 2001 ; Chirumamilla et al, 2002 ; Peters et al, 2018 ; Villasana et al, 2019 ), but only a few papers look at DG neurogenesis at a short-term time point post-mTBI, and the results are mixed ( Wang et al, 2016 ; Neuberger et al, 2017 ; Tomura et al, 2020 ). To address this knowledge gap, the neurogenic regions of the DG (SGZ, GCL) from Sham and LFPI mice were assessed 3 dpi for indices of proliferation (Ki67+ and BrdU+ cell number) and neuroblasts/immature neurons (DCX+ cell number).…”

Impact of Traumatic Brain Injury on Neurogenesis

“…The disparate effects appear dependent on timing and length of drug administration. After CCI, ketamine increased cell proliferation in the SGZ, decreased the number of newborn neurons, and ameliorated post-CCI cognitive deficits (Peters et al, 2018) suggesting that despite neurotoxic concerns, there may be beneficial effects. Indeed, ketamine is being evaluated as a promising therapy to halt SDs after TBI (Carlson et al, 2018; Hartings et al, 2018).…”

Coadministration of Ketamine and Perampanel Improves Behavioral Function and Reduces Inflammation in Acute Traumatic Brain Injury Mouse Model

“…Ketamine is also reported to inhibit NO synthesis thus exerting vasoconstrictive impact resulting in hemodynamic stability [ 30 ]. It has also shown to affect hippocampal cell proliferation after TBI leading to neurogenesis which led to better learning and behavior in mice with TBI [ 31 ].…”