Glutamate Network Function is Altered Following Traumatic Brain Injury

Traumatic brain injury (TBI) is a major risk factor for the onset of epilepsy. Although disruptions in cortical circuitry are associated with TBI, the precise mechanisms by which neuronal reorganization leads to altered glutamatergic network function remain unknown. In this study, we investigated how disruptions in cortical circuitry affect the spatial and temporal parameters of glutamate release following controlled cortical impact (CCI), a model of TBI. Using a novel glutamate biosensor, we were able to optically map cortical glutamate release and simultaneously record field potentials in cortical slices. 10 week old C57/B6 mice underwent CCI, and cortical slices were obtained 2-4 weeks post-injury. Results were compared to slices from sham and age-matched naïve mice. We demonstrate that extracellular glutamate signaling, epileptiform activity, and spontaneous activity are increased in CCI cortex compared to controls. Amplitude, duration, area, and high frequency activity of evoked field responses measured at threshold stimulation and after disinhibition with GABAzine suggest that network function is altered and GABAergic inhibition is compromised in CCI injured cortex. Furthermore, extracellular glutamate was released in a layer-specific manner, originating proximal to the site of injury and spreading distally into cortical layers II/III.  Our data suggest that cortical neurotransmission is altered following TBI. Increased glutamate signal and changes in network function parameters in CCI cortex suggest that altered glutamate release and loss of GABAergic control both contribute to changes in glutamate network function following TBI. We conclude that cortical reorganization resulting from TBI leads to increased network excitability by altering glutamatergic function.