Blast Wave Exposure Impairs Memory and Decreases Axon Initial Segment Length

Abstract

Exposure to a blast wave has been proposed to cause mild traumatic brain injury (mTBI), with symptoms including altered cognition, memory, and behavior. This idea, however, remains controversial, and the mechanisms of blast-induced brain injury remain unknown. To begin to resolve these questions, we constructed a simple compressed air shock tube, placed rats inside the tube, and exposed them to a highly reproducible and controlled blast wave. Consistent with the generation of a mild injury, 2 weeks after exposure to the blast, we found that motor performance was unaffected, and a panel of common injury markers showed little or no significant changes in expression in the cortex, corpus callosum, or hippocampus. Similarly, we were unable to detect elevated spectrin breakdown products in brains collected from blast-exposed rats. Using an object recognition task, however, we found that rats exposed to a blast wave spent significantly less time exploring a novel object when compared with control rats. Intriguingly, we also observed a significant shortening of the axon initial segment (AIS) in both the cortex and hippocampus of blast-exposed rats, suggesting altered neuronal excitability after exposure to a blast. A computational model showed that shortening the AIS increased both threshold and the interspike interval of repetitively firing neurons. These results support the conclusion that exposure to a single blast wave can lead to mTBI with accompanying cognitive impairment and subcellular changes in the molecular organization of neurons.

Axon Initial Segment–Associated Microglia

“…We speculate that AXIS microglia may perform similar functions for chandelier neurons at the AIS in the adult, uninjured brain. This function would be consistent with recent studies showing that AIS properties are plastic and can be modified depending on neural activity (Grubb and Burrone, 2010;Kuba et al, 2010;Baalman et al, 2013). In this case, AXIS microglia may alter neuronal activity by removing GABAergic synapses that, depending on the state of the neuron being modified, could increase or decrease AIS excitability.…”

“…A subset of "satellite" microglia associate with the AIS A variety of nervous system injuries can dismantle or remodel the AIS (Schafer et al, 2009;Kuba et al, 2010;Baalman et al, 2013;Hinman et al, 2013). Since microglia are activated by nervous system injury, we reasoned that they might also disrupt the AIS.…”

“…Immunostaining was performed on 35 m mounted brain sections as described previously (Baalman et al, 2013). Briefly, animals were killed with an overdose of isoflurane.…”

“…For all quantification, 20ϫ (0.8 numerical aperture) z-stacks were taken. Automated AIS quantification was described previously (Baalman et al, 2013). All other image analysis was performed using ImageJ.…”

A Novel Closed-Head Model of Mild Traumatic Brain Injury Using Focal Primary Overpressure Blast to the Cranium in Mice

“…19,20,[22][23][24][25][26]28,[30][31][32][33][128][129][130][131][132][133] These approaches avoid the severe focal contusive brain injury associated with open-skull TBI models, while a single exposure, depending on the blast pressure, can yield axonal injury, microglial activation, edema, and cognitive, emotional, and visual deficits, 20,23,24,26,28,30,31,33,[128][129][130][131]133,134 similar to those observed with our focal blast model. For example, significant rotarod motor deficits and axonal swellings have been reported for 2 weeks after a whole body 15-psi blast in mice, 19,24 and hippocampal neuron loss has been reported in rats 2 weeks after whole body 18-psi blast.…”