A role for decorin in improving motor deficits after traumatic brain injury.

• Quantification of tissue glycosaminoglycans via mass spectrometry provides unique insight into extracellular matrix remodeling after TBI. • Decreases in N-sulfated heparan sulfate, 4S and 2S/4S chondroitin sulfate, and increases in 0S chondroitin sulfate were observed 24 h after injury, which normalized 7d after injury. • Increases in total heparan sulfate, chondroitin sulfate, and hyaluronan were observed at the site of injury after 7d. • Unbiased transcriptomics analyses revealed upregulation of the proteoglycans glypican-3 and decorin, and the biosynthesis enzyme hyaluronan synthase 2 at 7d post-injury. These transcriptional changes may be responsible for observed increases in glycosaminoglycans. • Behavioral assessment of Dcn−/− mice 7d post-injury suggests a protective role for decorin upregulation following TBI. Traumatic brain injury (TBI) is the leading cause of death and disability due to injury worldwide. Extracellular matrix (ECM) remodeling is known to significantly contribute to TBI pathophysiology. Glycosaminoglycans, which are long-chain, variably sulfated polysaccharides abundant within the ECM, have previously been shown to be substantially altered after TBI. In this study, we sought to delineate the dynamics of glycosaminoglycan alterations after TBI and discover the precise biologic processes responsible for observed glycosaminoglycan changes after injury. We performed state-of-the art mass spectrometry on brain tissues isolated from mice after TBI or craniotomy-alone. We observed dynamic changes in glycosaminoglycans at Day 1 and 7 post-TBI, with heparan sulfate, chondroitin sulfate, and hyaluronan remaining significantly increased after a week vis-à-vis craniotomy-alone tissues. We did not observe appreciable changes in circulating glycosaminoglycans in mice after experimental TBI compared to craniotomy-alone nor in patients with TBI and severe polytrauma compared to control patients with mild injuries, suggesting increases in injury site glycosaminoglycans are driven by local synthesis. We subsequently performed an unbiased whole genome transcriptomics analysis on mouse brain tissues 7 days post-TBI and discovered a significant induction of hyaluronan synthase 2, glypican-3, and decorin. The functional role of decorin after injury was further examined through multimodal behavioral testing comparing wild-type and Dcn −/− mice. We discovered that genetic ablation of Dcn led to an overall negative effect of TBI on function, exacerbating motor impairments after TBI. Collectively, our results provide a spatiotemporal characterization of post-TBI glycosaminoglycan alterations in the brain ECM and support an important adaptive role for decorin upregulation after TBI. [ABSTRACT FROM AUTHOR]