Mechanisms of neuronal dysfunction in mild traumatic brain injury

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The career development plan described in this application is an essential step in fulfilling the long-term goals of the applicant of developing novel therapeutics for Veterans suffering from traumatic brain injury (TBI)-mediated visual loss and cognitive dysfunctions and becoming an independent investigator in the VA system. The research objective of this proposal is to identify compounds that treat blast-induced central nervous system dysfunctions using a combination of molecular, electrophysiologic and pharmacologic tools. The experiments will be performed using a mouse model developed at the Iowa City Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss (CPTVL) that has an ocular phenotype (retinal ganglion cell damage), and neurological deficits (learning, memory and coordination problems) present in humans. Mild TBI generates abnormal neuronal activity in the mouse model. At molecular level, the abnormal neuronal function could be the result of changes in the receptors of the main inhibitory neurotransmitter γ- aminobutyric acid (GABA). The first aim is to identify molecular changes in the expression, composition and localization of GABAA receptors in the retina and the brain of mice exposed to blast. The second aim is to find therapeutic agents that mitigate the abnormal firing activity of retinal ganglion cells that we have discovered to occur following blast-induced mild TBI. Electrophysiologic and pharmacologic tools will be used to test the effects of GABAA receptor targeting pharmacologic agents on neuronal activity to establish if they can restore proper function after mild TBI. The GABAA receptors can be targeted by a wide variety of well-characterized therapeutic agents (benzodiazepines, barbiturates, neurosteroids and inhaled anesthetics) that modulate their function. By defining the molecular and functional changes in the GABAA receptors induced by blast-mediated TBI, drugs that can compensate for the alterations in the GABAergic system can be identified and tested. Normalizing the neuronal activity and preventing the death of neurons, which we assume, ultimately, occurs in neurons exhibiting abnormal firing patterns, will result in preserved visual and cognitive functions. To ensure the clinical applicability of the research performed and that the applicant learns the necessary tools and skills to perform basic research with strong implications for translation into clinical practice, one of the mentors is a practicing psychiatrist. The training and mentoring plans also include interactions with the CPTVL Investigators, including a neuro-ophthalmologist, the Director of our Center, and the scientists and medical doctors associated with The Wynn Institute for Vision Research and the Iowa Institute for Clinical and Translational Science.