Introduction: Traumatic brain injury (TBI) is a potentially devastating condition affecting millions of people each year, which can burden survivors with memory deficits, depression, emotional lability and loss of... [ view full abstract ]
Introduction:
Traumatic brain injury (TBI) is a potentially devastating condition affecting millions of people each year, which can burden survivors with memory deficits, depression, emotional lability and loss of independence. TBI induces a dramatic neurogenic response in the hippocampus with unknown longer-term consequences: new neurons may compensate by assuming the functions of disrupted circuits, or interfere with hippocampal function, as injury-generated neurons have aberrant positioning and branching phenotypes. As anesthetic and sedative drugs are known to modulate neurogenesis, here we evaluate how ketamine-induced modulation of NMDA receptors, which are known to affect neurogenesis, impact the production of adult-born neurons and behavioral outcomes after TBI in mice.
Methods:
In accordance with IACUC-approved protocols, wild-type mice underwent controlled cortical impact (CCI) model of TBI vs. sham (non-injury), followed by immediate initiation of ketamine or vehicle infusion via osmotic drug pump. Pumps were removed after 1 week. Neurogenesis and other cellular responses were assessed using immunohistochemistry at 2 and 6 weeks post-injury, to evaluate mitotic activity (BrdU) and the production of new neurons (doublecortin & NeuN), astrocytes (GFAP) and microglia (Iba1) in the granule cell layer of the hippocampal dentate gyrus. Behavioral testing of hippocampal dependent tasks was accomplished via Morris Water Maze (MWM) Reversal test at 4 weeks after injury.
Results:
CCI induced dramatic cellular proliferation in vehicle-treated animals. Injury-induced neurogenesis was not apparent at the 2-week time point but was significantly increased by 6 weeks, suggesting increased survival of injury-born neurons; ketamine exposure abolished this effect on neurogenesis but not the effect on overall cell proliferation. CCI increased the production of new astrocytes in vehicle-exposed mice and increased new microglia in the ketamine exposed group. Behavioral testing revealed impaired spatial learning and memory after CCI; ketamine exposure prevented this deficit.
Conclusions:
CCI triggers a robust proliferative response in the dentate of the hippocampus characterized by increased neuron and astrocyte creation. However, behavioral testing revealed impaired hippocampal learning and memory in these mice. Ketamine administered in the immediate post-injury period reduced this neurogenic and astrogenic response; but surprisingly, these mice performed equivalently to non-injured mice in MWM Reversal. These results suggest that, rather than improving function, injury induced neurogenesis could impair performance in certain hippocampus-dependent tasks, possibly by preventing the generation of aberrantly projected new granule cells.
