Transient Reductions in Serotonin Transporter Expression and Function Elicited by Blast‐Induced Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a leading cause of disability among civilians and the hallmark injury associated with modern military conflicts around the globe. TBI is associated with enduring psychiatric comorbidities such as post‐traumatic stress disorder (PTSD), major depressive disorder (MDD), anxiety and social dysfunction. The molecular mechanisms by which TBI results in the generation of neuropsychiatric disorders are currently not well understood, however these disorders have classically been linked to serotonin (5‐HT) signaling. The single largest determinant of the cessation of 5‐HT signaling is the serotonin transporter (SERT), a Na+/Cl−‐dependent transporter that is the target of clinically utilized serotonin reuptake inhibitors (SRI’s) and is highly expressed on 5‐HT neurons located within the raphe nucleus of the mammalian CNS. We hypothesized that TBI results in alterations in the regional expression and/or function of SERT within the CNS. To test this hypothesis, we utilized a combination of a model for blast‐induced TBI, scaled in intensity and duration for murine subjects in combination with adult, wildtype C57Bl/6J mice. Subjects received a single, blast‐induced TBI or sham treatment followed by sample collection at 3, 10 and 30 days post‐injury (dpi). Righting reflex time (RRT) was recorded for all subjects immediately following injury. TBI was found to significantly increase RRT as compared to sham treatment, indicative of a loss of consciousness in rodent subjects. Western blot analysis or [3H] 5‐HT synaptosomal uptake assays were utilized to determine SERT protein expression levels and SERT‐mediated 5‐HT uptake post‐injury, respectively. Reductions in SERT protein expression were found in the dorsal raphe nucleus (DRN) 3 dpi. Concomitant reductions in SERT‐mediated midbrain synaptosomal [3H] 5‐HT uptake were found 3 dpi. These effects were found to be time dependent as SERT protein expression normalized by 10 dpi. Further, no post‐injury differences in SERT expression or [3H] 5‐HT uptake in the prefrontal cortex (PFC), a region of dense 5‐HT innervation were found. Data contained here are the first to show that blast‐induced TBI results in transient and regional alterations in SERT expression/function. A more thorough understanding of the temporal regulation of SERT function following neurotrauma may allow for better utilization of currently available pharmacotherapies for the treatment of TBI‐elicited neuropsychiatric disorders.Support or Funding InformationStudies were supported by the PhRMA Foundation, the University of Cincinnati ASPET SURF Program and the University of Cincinnati.