Traumatic brain injury (TBI), a leading cause of death and disability in the United States, causes potentially preventable damage in part through the dysregulation of neural calcium levels. This dysregulation likely affects the activity of the calcium-sensitive phosphatase, calcineurin, with serious implications for neural function. To test this possibility, the present study characterized the role of calcineurin in a rat model of brain trauma, the lateral fluid percussion injury model. Golgi-Cox histochemistry revealed an acute post-TBI loss and delayed overgrowth of dendritic spines on principal cortical cells. The spine loss appeared to require calcineurin activity, since administering a calcineurin inhibitor, FK506, 1 hour after TBI prevented the spine loss. Additional experiments showed how calcineurin activity might be related to the spine loss. Specifically, Western blots and enzyme activity assays revealed an acute increase in the cortical activity of calcineurin and its downstream effector, the actin-depolymerizing protein, cofilin. The cofilin activation was blocked by the same FK506 treatment that prevented spine loss, suggesting a relationship between cofilin activation and spine loss. To investigate long-term consequences of calcineurin activation after TBI, rats were administered FK506 (Tacrolimus) 1 hour after TBI and then monitored for spontaneous seizure activity months later. Acute post-TBI treatment with FK506 reduced the frequency of late non-convulsive seizures but did not prevent late convulsive seizures, cortical atrophy, or thalamic damage. The results of the present study implicate calcineurin in the acute dendritic remodeling and late non-convulsive seizures that occur after TBI. Importantly, these findings reveal calcineurin as a potential therapeutic target in the treatment of TBI and its sequalae.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-3651 |
| Date | 14 February 2012 |
| Creators | Campbell, John |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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