title: JAK/STAT pathway regulation of GABAA receptor expression after differing severities of experimental TBI.
abstract: Synaptic inhibition in the adult brain is primarily mediated by the γ-aminobutyric acid (GABA) type A receptor (GABA(A)R). The distribution, properties, and dynamics of these receptors are largely determined by their subunit composition. Alteration of subunit composition after a traumatic brain injury (TBI) may result in abnormal increased synaptic firing and possibly contribute to injury-related pathology. Several studies have shown that the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway can alter GABA(A)R subunit expression. The present study investigated changes in JAK/STAT pathway activation after two different severities of experimental TBI in the mouse using the controlled cortical impact (CCI) model. It also investigated whether modulating the activation of the JAK/STAT pathway after severe controlled cortical impact (CCI-S) with a JAK/STAT inhibitor (WP1066) alters post-traumatic epilepsy development and/or neurological recovery after injury. Our results demonstrated differential changes in both the activation of STAT3 and the expression of the GABA(A)R α1 and γ2 subunit levels that were dependent on the severity of the injury. The change in the GABA(A)R α1 subunit levels appeared to be at least partly transcriptionally mediated. We were able to selectively reverse the decrease in GABA(A)R α1 protein levels with WP1066 treatment after CCI injury. WP1066 treatment also improved the degree of recovery of vestibular motor function after injury. These findings suggest that the magnitude of JAK/STAT pathway activation and GABA(A)R α1 subunit level decrease is dependent on injury severity in this mouse model of TBI. In addition, reducing JAK/STAT pathway activation after severe experimental TBI reverses the decrease in the GABA(A)R α1 protein levels and improves vestibular motor recovery.
authors.affiliation: Neuroscience Program, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States. Electronic address: draible09@gmail.com.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Raible
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States. Electronic address: Lauren.Frey@ucdenver.edu.
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Frey
authors.affiliation: Division of Neurology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States. Electronic address: Yasmin.cruzdelangel@ucdenver.edu.
authors.forename: Yasmin Cruz
authors.initials: YC
authors.lastname: Del Angel
authors.affiliation: Division of Neurology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States. Electronic address: Jessica.Carlsen@ucdenver.edu.
authors.forename: Jessica
authors.initials: J
authors.lastname: Carlsen
authors.affiliation: Division of Neurology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States. Electronic address: Dana.hund@ucdenver.edu.
authors.forename: Dana
authors.initials: D
authors.lastname: Hund
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United States. Electronic address: srussek@bu.edu.
authors.forename: Shelley J
authors.initials: SJ
authors.lastname: Russek
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky, MS508 Chandler Medical Center, 800 Rose Street, Lexington, KY 40536, United States. Electronic address: bret.smith@uky.edu.
authors.forename: Bret
authors.initials: B
authors.lastname: Smith
authors.affiliation: Neuroscience Program, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States; Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States; Division of Neurology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States; Children's Hospital Colorado, Aurora, CO, United States. Electronic address: Amy.Brooks-Kayal@childrenscolorado.org.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Brooks-Kayal
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004569:Electroencephalography; D005106:Exploratory Behavior; D005786:Gene Expression Regulation / Q000502:physiology; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D021641:Recognition, Psychology; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D011963:Receptors, GABA-A; D050791:STAT Transcription Factors; D053612:Janus Kinases
keywords: GABA(A) receptor; JAK/STAT pathway; STAT3; Traumatic brain injury