Controlled Cortical Impact Increases the Relative Abundance of Chondroitin 6‐Sulfate in the Lateral Posterior Thalamus

Abstract

The brain is limited in its capacity to repair and reorganize neural networks following traumatic brain injury (TBI). Sulfated chondroitin sulfate (CS)‐glycosaminoglycan (GAG) extracellular matrix chains are known to influence formation and maintenance of neural networks, and maladaptive changes to the CS‐GAG abundance or sulfation pattern are associated with neurocircuit dysfunction. Recent reports indicate that TBI can alter the sulfation pattern of CS‐GAG chains, however, little is known about the anatomical and functional relevance of these changes. In this study, adult male C57BL/6 mice were subjected to a TBI via a controlled cortical impact (CCI) to the somatosensory cortex (SSC), where an established thalamocoritcal connection between the SSC and the lateral posterior thalamus (LPT) exists for sensorimotor function. At 7 and 28 days following CCI, immunofluorescence analysis of the ipsilateral, but not the contralateral LPT revealed a significant increase in the 6S‐CS sulfated GAG marker CS‐56. To analyze the relative changes in all CS‐GAG sulfation, CS disaccharides were released from both ipsilateral and contralateral SSC and LPT regions and quantified using a recently optimized LC‐MS/MS + MRM technique, which can differentiate between the relative abundance of five specific CS isomers (Δ4S‐, Δ6S‐, Δ4S6S‐, Δ2S6S‐, Δ0S‐CS) and dermatan sulfate (Δ2S4S‐DS). Here, we show that both the ipsilateral SSC and LPT exhibited higher percentages of Δ6S‐CS disaccharides compared to the contralateral brain regions, as well as the sham control brain regions. To determine whether the increase in 6S‐CS abundance in the SSC and LPT associate with sensorimotor function, CCI mice were subjected to the rotarod task to measure sensorimotor performance. Mice exposed to CCI exhibited a decrease in their latency to fall from the rotarod, which inversely correlated to the percentage of Δ6S‐CS. Collectively, these data suggest that CCI alters the CS‐GAG sulfation pattern within the thalamocortical circuitry, and these changes may contribute to persistent sensorimotor dysfunction. Future studies will investigate novel therapeutic interventions targeting CS‐GAG chains to potentially improve outcomes from TBI.Support or Funding InformationR01GM127579 to M.G.R01AG046619 to W.B.F32DK12266201 to K.A.