Abstracts

Rationale: Numerous studies have suggested that traumatic brain injury (TBI) significantly increases the chance of developing temporal lobe epilepsy (TLE). Understanding the cellular mechanisms of the development of epilepsy after a TBI could lead to improved treatments for TBI patients and offer insights into the prevention of TLE. Inhibitory neurotransmission is altered in patients with TLE. This alteration has been correlated with a long-term decrease in the expression of the GABAA receptor 1 gene (Gabra1) in the hippocampus. The Janus Kinase / Signal Transducer and Activator of Transcription (JaK/STAT) pathway has been shown in other models of acquired TLE to drive a decrease in transcription of Gabra1 by increasing the transcription of inducible cAMP element repressor (ICER), which decreases the expression of Gabra1 by binding and deactivating the Gabra1 promoter. This study investigated whether the JaK/STAT pathway is activated and if there were any alterations in GABAA receptor levels after experimental TBI, which could contribute to the altered neuronal excitability seen in TLE patients. Methods: Controlled Cortical Impact (CCI) was performed on adult male mice to generate a TBI. Thirty and ninety minutes after CCI, mice were given 75 mg of a JaK/STAT inhibitor (WP1066) or vehicle and sacrificed at 6 hours, 24 hours, 48 hours, 72 hours, 1 week or 12 weeks after injury. Whole hippocampi were dissected at the above time points and protein and mRNA levels for the GABAA receptor subunits and JaK/STAT related proteins were analyzed. Results: The JaK/STAT pathway is activated after experimental TBI using the CCI model in mice, as indicated by the increased phosphorylation of STAT3. WP1066 inhibited JaK/STAT pathway activation 6, 24 and 48 hours after injury. After CCI, levels of the 1 subunit of the GABAA receptor were decreased 24 and 48 hours post injury and levels of several other GABAA receptor subunits were altered 12 weeks after injury. With post-injury administration of WP1066, GABAA receptor 1 subunit levels were returned to sham operated control levels at 24 and 48 hours post CCI. Conclusions: The activation of the JaK/STAT pathway after CCI may regulate the decreased level of the GABAA receptor 1 subunit and may contribute to the development of epilepsy after a cerebral injury. Future studies will determine if blocking this pathway with WP1066 prevents the decrease levels of GABAA receptor 1 subunit chronically and prevents the development of epilepsy after a TBI.