Abstracts

Rationale: Traumatic brain injury (TBI) affects ∼500,000 U.S. military members in the last two decades, often leading to post-traumatic epilepsy (PTE). At present, there is no effective preventive strategies and treatment is largely symptomatic. To address this gap, we focus our research on the thalamus since it plays a crucial part in seizure generalization and in the signaling between the cortex and subcortical structures necessary to identify how TBI has affected the transport of glutamate and GABA in thalamic glial cells. We also explore the therapeutic potential of a non-invasive modality such as repetitive transcranial magnetic stimulation (rTMS) on neuronal excitability. We aim to identify cellular mechanisms of rTMS in restoration of inhibitory control as innovative intervention strategy to prevent PTE.


Methods: We induced repetitive, diffuse TBI in 12-16-week-old male and female C57Bl/6 mice to simulate military-like conditions. This model recapitulates key human non-lesional TBI characteristics that include loss of neurological reflexes and the onset of spontaneous, unprovoked, recurrent seizures. rTMS was delivered for 14 days post-TBI. Immunohistochemical assays were conducted at 14 days post-TBI focusing on key thalamic glial markers: gaba transporter-3 (GAT3), glutamate transporter-1 (GLT1), and ionized calcium binding adaptor molecule-1 (IBA1), to evaluate the acute effects of TBI and the therapeutic effects of rTMS on GABA and glutamate transport, and microglial activation respectively.


Results: Our study revealed significant changes in thalamic glial cell responses to rdTBI and rTMS treatment. Specifically, GAT3 expression, crucial for GABAergic function, significantly decreased following rdTBI, indicating impaired uptake of extracellular inhibitory neurotransmitter which could contribute to loss of function in preventing excessive neuronal excitation and generalization. However, rTMS treatment post-rdTBI partially restored GAT3 levels, highlighting its potential therapeutic effect on GABAergic pathways. GLT1 expression remained unchanged, suggesting that glutamate transport mechanisms in the thalamus are not significantly affected by rdTBI or rTMS under these conditions. IBA1 levels increased significantly after rdTBI, indicating an inflammatory response and increased microglial activity. rTMS significantly mitigated this response, suggesting its potential anti-inflammatory effects.


Conclusions: The results of present studies underlined putative role of thalamus in PTE pathogenesis following rdTBI and potential of rTMS as dual action therapeutic strategy with ability of modification of inhibitory neurotransmitter system and in reduction of neuroinflammation in prevention of PTE progression. Our study demonstrates a further research path for the need to target neuromodulation therapy in reducing PTE which will significantly improve management of TBI in context of military and civilian populations.


Funding: U.S. Army CDMRP Virtual Post-Traumatic Epilepsy Research Center Faculty Award #HT94252410116, FIU Wallace Coulter Foundation SEED Grant, FIU BME Startup Fund.