title: Traumatic Brain Injury Increases Cortical Glutamate Network Activity by Compromising GABAergic Control.
abstract: Traumatic brain injury (TBI) is a major risk factor for developing pharmaco-resistant epilepsy. Although disruptions in brain circuitry are associated with TBI, the precise mechanisms by which brain injury leads to epileptiform network activity is unknown. Using controlled cortical impact (CCI) as a model of TBI, we examined how cortical excitability and glutamatergic signaling was altered following injury. We optically mapped cortical glutamate signaling using FRET-based glutamate biosensors, while simultaneously recording cortical field potentials in acute brain slices 2-4 weeks following CCI. Cortical electrical stimulation evoked polyphasic, epileptiform field potentials and disrupted the input-output relationship in deep layers of CCI-injured cortex. High-speed glutamate biosensor imaging showed that glutamate signaling was significantly increased in the injured cortex. Elevated glutamate responses correlated with epileptiform activity, were highest directly adjacent to the injury, and spread via deep cortical layers. Immunoreactivity for markers of GABAergic interneurons were significantly decreased throughout CCI cortex. Lastly, spontaneous inhibitory postsynaptic current frequency decreased and spontaneous excitatory postsynaptic current increased after CCI injury. Our results suggest that specific cortical neuronal microcircuits may initiate and facilitate the spread of epileptiform activity following TBI. Increased glutamatergic signaling due to loss of GABAergic control may provide a mechanism by which TBI can give rise to post-traumatic epilepsy.
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, SC201, Boston, MA 02111, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cantu
authors.affiliation: Department of Neuroscience, Alzheimer's Disease Research Laboratory, Tufts University School of Medicine, A305, Boston, MA 02111, USA.
authors.forename: Kendall
authors.initials: K
authors.lastname: Walker
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, SC201, Boston, MA 02111, USA Program in Neuroscience at the Sackler School of Biomedical Sciences, Tufts University.
authors.forename: Lauren
authors.initials: L
authors.lastname: Andresen
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, SC201, Boston, MA 02111, USA Current address: Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, SC201, Boston, MA 02111, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hampton
authors.affiliation: Department of Neuroscience, Alzheimer's Disease Research Laboratory, Tufts University School of Medicine, A305, Boston, MA 02111, USA.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Tesco
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, SC201, Boston, MA 02111, USA.
authors.forename: Chris G
authors.initials: CG
authors.lastname: Dulla
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000503:physiopathology; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D059330:GABAergic Neurons / Q000473:pathology / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism*; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000473:pathology / Q000503:physiopathology; D010320:Parvalbumins / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D010320:Parvalbumins; C493396:Slc1a2 protein, mouse; C493393:Slc1a3 protein, mouse; D018698:Glutamic Acid; D013004:Somatostatin
keywords: cortical hyperexcitability; epilepsy; glutamate signaling; network reorganization; traumatic brain injury