Bailey Baker

 Introduction.  Traumatic brain injury (TBI) affects over 2.5 million people annually in the United States, with mild or diffuse TBI representing 75-86% of the injury pool¹. Effects of TBI include disturbed cognition, behavior, emotion, and motor function, due to the morphologic, biochemical, and physiologic insults to neural brain tissue^1,3.  This neuronal damage can lead to CNS hyperexcitability, a hallmark of post-traumatic epilepsy (PTE)⁶. PTE presents clinically as two or more “unprovoked” or “late” seizures 7 days or greater after a TBI, and manifests as periods of unresponsiveness, altered awareness, disorientation, or motor symptoms such as automatisms, jerking, or twitching³.  Studies have shown that reactive astrogliosis is a critical biochemical event within the CNS following repeated mild TBI, and leads to physiologic changes in glutamate and potassium channels that decrease astrocytic ability to maintain excitation-inhibition homeostasis^5,6,8.  Methods.  Reactive astrogliosis was induced in mice without breaking the blood-brain-barrier through conditional deletion of β1-integrin (Itgβ1) in radial glia. Intracranial recording electrodes were inserted in vivo, and used to monitor seizure activity, followed by removal and fixation of brain tissue. A combination of immunohistochemistry and Western blot against astrocytic potassium (Kir4.1) and glutamate (Glt-1) transporters was utilized to assess whether synaptic uptake of these chemicals was impaired in β1^−/− mice when compared to non-reactive controls⁶. Results.  EEG of β1^−/− mice showed the development of spontaneous seizures and epileptic foci^5,6. Hsp90b was upregulated as astrocytes transitioned from a quiescent to a reactive state, and promoted the association between Glt-1 and the 20S proteasome⁷. This led to Glt-1 degradation and reduced glutamate uptake at the synaptic cleft. Interleukin 1beta (IL-1b), an inflammatory cytokine released in response to mild TBI, caused suppression of Kir4.1 mRNA expression^10,11. Lack of Kir4.1 potassium channels decreased the astrocytes’ ability to keep synaptic K+ low, bringing the neuron closer to the firing threshold and rendering it more excitable^2,11. Additionally, suppression of Kir4.1 caused an overall depolarization of the astrocyte and impeded the translocation step of glutamate transport by Glt-1, thus perpetuating hyperexcitability by further depressing extracellular glutamate clearance^2,4,11.  Conclusions.  Changes in protein expression induced by TBI reduces astrocytes’ ability to perform physiologic homeostatic functions via glutamate and potassium transporters at neuronal synapses^5,6,8. Excess excitation molecules residing in synaptic clefts results in CNS hyperexcitability, and may manifest as PTE⁶. Targeting mechanisms of Glt-1 and Kir4.1 degradation may provide therapeutic and prophylactic treatment options by restoring the balance between neuronal excitation and inhibition^3,9.

1. Centers for Disease Control and Prevention. (2015). Report to Congress on Traumatic Brain Injury in the United States: Epidemiology and Rehabilitation. National Center for Injury Prevention and Control; Division of Unintentional Injury Prevention. Atlanta, GA.
2. Gupta RK, Prasad S. Early down regulation of the glial Kir4.1 and GLT-1 expression in pericontusional cortex of the old male mice subjected to traumatic brain injury. Biogerontology. 2013;14(5):531-541. doi:10.1007/s10522-013-9459-y
3. Hung, C., & Chen, J. W. (2012). Treatment of Post-Traumatic Epilepsy. Current Treatment Options in Neurology,14(4), 293-306. doi:10.1007/s11940-012-0178-5
4. Kucheryavykh YV, Kucheryavykh LY, Nichols CG, et al. Downregulation of Kir4.1 inward rectifying potassium channel subunits by RNAi impairs potassium transfer and glutamate uptake by cultured cortical astrocytes. Glia. 2006;55(3):274-281. doi:10.1002/glia.20455
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6. Robel S, Buckingham SC, Boni JL, et al. Reactive astrogliosis causes the development of spontaneous seizures. J Neurosci. 2015;35(8):3330-45.
7. Sha L, Wang X, Li J, et al. Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy. The Journal of Experimental Medicine. 2016;214(2):547-563. doi:10.1084/jem.20160667
8. Shandra O, Winemiller AR, Heithoff BP, et al. Repetitive Diffuse Mild Traumatic Brain Injury Causes an Atypical Astrocyte Response and Spontaneous Recurrent Seizures. The Journal of Neuroscience. 2019;39(10):1944-1963. doi:10.1523/jneurosci.1067-18.2018
9. Soni N, Reddy B, Kumar P. GLT-1 transporter: An effective pharmacological target for various neurological disorders. Pharmacology Biochemistry and Behavior. 2014;127:70-81. doi:10.1016/j.pbb.2014.10.001
10. Wathen C, Janigro D. IL-1β associations with posttraumatic epilepsy development: A genetics and biomarker cohort study. Epilepsia. 2014;55(8):1313-1313. doi:10.1111/epi.12693
11. Zurolo E, Groot MD, Iyer A, et al. Regulation of Kir4.1 expression in astrocytes and astrocytic tumors: a role for interleukin-1 β. Journal of Neuroinflammation. 2012;9(1). doi:10.1186/1742-2094-9-280