Abstract
Traumatic brain injury (TBI) affects over 69 million people annually worldwide, and those with pre-existing depression have worse recovery. The molecular mechanisms that may contribute to poor recovery after TBI with co-morbid depression have not been established. TBI and depression have many commonalities including volume changes, myelin disruption, changes in proliferation, and changes in glutamatergic signaling. We used a well-established animal model of depression, the Wistar Kyoto (WKY) rat, to elucidate changes after TBI that may influence the recovery trajectory. We compared the histological and molecular outcomes in the hippocampal dentate gyrus after experimental TBI using the lateral fluid percussion injury (LFPI) in the WKY and the parent Wistar (WIS) strain. We showed that WKY had exaggerated myelin loss after LFPI and baseline deficits in proliferation. In addition, we showed that while after LFPI WIS rats exhibited glutamate receptor subunit changes, namely increased GluN2B, the WKY rats failed to show such injury-related changes. These differential responses to LFPI helped to elucidate the molecular characteristics that influence poor recovery after TBI in those with pre-existing depression and may lead to targets for future therapeutic interventions.
Highlights
We examined the glutamate receptor subunit expression in the hippocampal dentate gyrus, as we have previously shown changes in glutamate signaling in the hippocampus and because of the recognized importance of this neurotransmitter system in both Traumatic brain injury (TBI) and depression [20,21,26]
We have shown that Wistar Kyoto (WKY) animals showed deficits in cognition, exhibited a lack of GluN2B receptor subunit protein expression changes after injury, and demonstrated a low Ki-67+ cell count in the dentate gyrus when compared with the WIS
The WKY has historically been a good model for depression, as the strain shows depressive-like responses to novel stress in emotional behavior testing [39]
Summary
Major depressive disorder (MDD) is associated with significant histological and biochemical changes, especially in the hippocampus These changes are associated with hippocampal dysfunction, which may interfere with recovery and lead to worse outcomes [7]. This activity spreads across the contiguous cortex and can be induced in many brain regions, including the hippocampus [26] These spreading depolarizations have been shown to be a prominent pathology in patients with TBI and prognosticate a worse outcome [27,28,29]. We examined the glutamate receptor subunit expression in the hippocampal dentate gyrus, as we have previously shown changes in glutamate signaling in the hippocampus and because of the recognized importance of this neurotransmitter system in both TBI and depression [20,21,26]. TBI, yet WKY failed to show such changes, which may represent an inappropriate injury response and a target for intervention in TBI with co-morbid depression
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