A Mouse Model of Repetitive Blast Traumatic Brain Injury Reveals Post-Trauma Seizures and Increased Neuronal Excitability

Abstract

Repetitive blast traumatic brain injury (TBI) affects numerous soldiers on the battlefield. Mild TBI has been shown to have long-lasting effects with repeated injury. We have investigated effects on neuronal excitability after repetitive, mild TBI in a mouse model of blast-induced brain injury. We exposed mice to mild blast trauma of an average peak overpressure of 14.6 psi, repeated across three consecutive days. While a single exposure did not reveal trauma as indicated by the glial fibrillary acidic protein indicator, three repetitive blasts did show significant increases. As well, mice had an increased indicator of inflammation (Iba-1) and increased tau, tau phosphorylation, and altered cytokine levels in the spleen. Videoelectroencephalographic monitoring 48 h after the final blast exposure demonstrated seizures in 50% (12/24) of the mice, most of which were non-convulsive seizures. Long-term monitoring revealed that spontaneous seizures developed in at least 46% (6/13) of the mice. Patch clamp recording of dentate gyrus hippocampus neurons 48 h post-blast TBI demonstrated a shortened latency to the first spike and hyperpolarization of action potential threshold. We also found that evoked excitatory postsynaptic current amplitudes were significantly increased. These findings indicate that mild, repetitive blast exposures cause increases in neuronal excitability and seizures and eventual epilepsy development in some animals. The non-convulsive nature of the seizures suggests that subclinical seizures may occur in individuals experiencing even mild blast events, if repeated.

Seizures are a druggable mechanistic link between TBI and subsequent tauopathy

“…Here, we revealed for the first time a snapshot of neurons becoming active at the moment of TBI. Our results demonstrated an increase in neuronal excitability upon TBI, which may contribute to the frequency of post-traumatic seizures observed in our model, other blast TBI models and TBI patients ( Bugay et al, 2020 ). The increases in neuronal activity were especially prominent in the hindbrain; this may be due to this region being susceptible to injury in our paradigm, and/or represent an output that is related to increased movement (e.g.…”

“…The post-traumatic seizures apparent in our TBI model led us to consider the neural events occurring during the TBI, and their potential bearing on the correlation between neural activity and tauopathy. Few studies examine how TBI impacts neuronal circuits, especially in vivo, and these typically consider events several hours or days after brain trauma ( Bugay et al, 2020 ). This may be of importance when considering evaluating the reasons behind the developments of post-traumatic seizures and epilepsy.…”

Blast Preconditioning Protects Retinal Ganglion Cells and Reveals Targets for Prevention of Neurodegeneration Following Blast-Mediated Traumatic Brian Injury

“…The effect of repetitive blast exposures on the brain has been less well characterized than for non–blast-mediated TBIs. Multiple blast exposures in preclinical models lead to increased blood–brain barrier permeability51 as well as seizures,52 in addition to axonal damage and white matter injury,32,53,54 compared to one single blast exposure. Laboratory models have shown decreased metabolic rate,55 which may lead to increased oxidative stress 56.…”

Modeling of post-traumatic epilepsy and experimental research aimed at its prevention

“…Similarly, in the penetrating ballistic-like injury model, electrographic waveforms of ictal and inter-ictal events are reported, but occur later after injury and less frequently compared to those occurring in other injury models ( 26 ). In the repetitive weight-drop model and in the repetitive blast model, only a subset of mice (44 and 46%, respectively) develop spontaneous recurrent seizures ( 27 ).…”