Novel Cellular Approach To Study Acute Neuronal Hyperexcitability In A Traumatic Brain Injury Model

Description

This project explores mechanisms underlying development of seizures in the immediateaftermath of traumatic brain injury (TBI). Early onset seizures are among the most seriousmorbidities with traumatic TBI. Yet our understanding of the mechanisms that precipitate earlyseizures is quite incomplete, in part, because most studies report changes in neuronal functionwhen biochemical and molecular studies indicate that significant changes in gene regulationand protein expression have already occurred. To address this gap in our understanding, wemodified an in vitro TBI stretch injury model using networks of cultured cortical neurons in whichinjury is confined to a localized area, but neuron electrical activity can be measured almostimmediately. Our novel finding is that hyperexcitability, i.e. dramatically increased spontaneousaction potential and bursting activity, is observed within minutes after stretch injury, but only in“non-injured” neurons located away from the injury site. This hyperexcitability in the non-injuredneurons is analogous to activity patterns in in vivo models of TBI where hyperexcitability isthought to precipitate seizure-like discharges. Because hyperexcitability is observed in non-injured neurons only, we hypothesize that reduced inhibitory neurotransmission from injuredneurons disinhibits electrical activity in surrounding non-injured neurons. To test thishypothesis, (1) we will determine whether acute hyperexcitability is due to changes in excitatoryor inhibitory neurotransmission from injured neurons or due to intrinsic changes in non-injuredneurons using electrophysiologic and histologic approaches. (2) We will determine how acutehyperexcitability in non-injured neurons arises from altered dynamics of adjoining injuredneurons using genetically-encoded membrane potential sensors to map spatiotemporalchanges in electrical activity in physically and functionally defined neurons. These data will beanalyzed to determine how stretch injury affects signal propagation and therefore informationdynamics in the neural network. Altogether, proposed experiments will allow us to establish anew in vitro model for TBI-induced seizures and, using state-of-the-art molecular techniques,gain an unprecedented understanding of how acute alterations in network function producehyperexcitability and post-traumatic seizures. In doing so, this project will highlight potentialmechanisms to explore in future experiments using in vitro and in vivo TBI models as well aspotential approaches to minimize early-onset seizures after TBI. Summary:
StatusFinished
Effective start/end date7/1/166/30/18

Funding

  • National Institutes of Health (NIH)

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Neurons
Seizures
Wounds and Injuries
Synaptic Transmission
Traumatic Brain Injury
Membrane Potentials
In Vitro Techniques
Proteins