Traumatic Brain Injury and Endocytosis: Reduced Rodent Hippocampal Endocytosis Proteins and Human Clathrin Light Chain Polymorphisms Are Associated with Impaired Neurological Outcomes After TBI

Traumatic brain injury (TBI) can result in enduring cognitive, emotional, and somatic impairments, which may be mediated in part by impaired synaptic function. Prior studies in experimental models of TBI have implicated molecular disturbances within the synaptic vesicular pool as a mediator of altered neurotransmission. Endocytosis maintains the pre-synaptic pool through recycling and replenishment of neurotransmitter-containing vesicles, and dysregulation of this mechanism is a plausible candidate for TBI-induced synaptic dysfunction. We sought to determine if TBI had a detrimental effect on clathrin-mediated endocytosis (CME)-associated proteins, a response underexplored. We hypothesized that the abundance of CME in the brain decreases in rats subjected to a controlled cortical impact (CCI) injury. Assessments of hippocampal CME proteins revealed similar responses to CCI in female and male rats with decreased hippocampal abundance of clathrin light chain, AP180, dynamin, and Rab5 at 14 days post-injury. While we did not directly test the role of CME modulation in this study, reductions in protein abundances were temporally aligned with neurobehavioral impairments in motor, spatial learning, and spatial memory performance, independent of sex. Sex-dependent differences were observed in the open-field testing. We also sought to examine if the presence of single nucleotide polymorphisms (SNPs) in clathrin genes were associated with outcomes in severe TBI patients. Human SNP analysis for clathrin light chain A (CLTA) revealed a minor allele (rs4879960) was associated with improved outcomes on the Glasgow Outcome Scale and Disability Rating Scale in severe TBI patients. These data provide insight into synaptic changes in CME proteins that show associational changes with cognitive impairments post-injury preclinically. This study identifies clinically relevant SNPs that are correlated with long-term outcomes post-TBI.