Primary Blast Exposure Increases Hippocampal Vulnerability to Subsequent Exposure: Reducing Long-Term Potentiation

Abstract

Up to 80% of injuries sustained by U.S. soldiers in Operation Enduring Freedom and Operation Iraqi Freedom were the result of blast exposure from improvised explosive devices. Some soldiers experience multiple blasts while on duty, and it has been suggested that symptoms of repetitive blast are similar to those that follow multiple non-blast concussions, such as sport-related concussion. Despite the interest in the effects of repetitive blast exposure, it remains unknown whether an initial blast renders the brain more vulnerable to subsequent exposure, resulting in a synergistic injury response. To investigate the effect of multiple primary blasts on the brain, organotypic hippocampal slice cultures were exposed to single or repetitive (two or three total) primary blasts of varying intensities. Long-term potentiation was significantly reduced following two Level 2 (92.7 kPa, 1.4 msec, 38.5 kPa·msec) blasts delivered 24 h apart without altering basal evoked response. This deficit persisted when the interval between injuries was increased to 72 h but not when the interval was extended to 144 h. The repeated blast exposure with a 24 h interval increased microglia staining and activation significantly but did not significantly increase cell death or damage axons, dendrites, or principal cell layers. Lack of overt structural damage and change in basal stimulated neuron response suggest that injury from repetitive primary blast exposure may specifically affect long-term potentiation. Our studies suggest repetitive primary blasts can exacerbate injury dependent on the injury severity and interval between exposures.

Primary blast injury causes cognitive impairments and hippocampal circuit alterations

“…Our observation that primary blast exposure causes broad changes in glial reactivity with no significant evidence of neuronal loss or degeneration is consistent with some past rodent (Svetlov et al, 2010) and porcine models of bTBI (Bauman et al, 2009; de Lanerolle et al, 2011), and some aspects of past in vitro work (Effgen et al, 2014; Effgen et al, 2015; Vogel et al, 2015). Similar to our data on hippocampal circuit alterations, we did not observe a significant dose response in glial reactivity between the lower- and higher-level blast overpressure loading.…”

“…Preclinical rodent studies show blast exposure will cause alterations in hippocampal microstructure, increases in different forms of phosphorylated Tau, reductions in axonal conduction velocity, and LTP deficits in the hippocampal circuitry after injury (Budde et al, 2013; Effgen et al, 2015; Goldstein et al, 2012; Huber et al, 2013; Vogel et al, 2015; Yin et al, 2014). We demonstrate that despite no clear sign of neuronal loss, blast exposure will reduce hippocampal network excitability in area CA1, and that these changes do not differ across these two blast exposure levels.…”

“…Drawing a direct connection from this human volunteer study to our work, though, is not easy because these human volunteers were involved in multiple exposures and we only examined a single blast exposure. Moreover, past work from our group shows that blast overpressure in vitro will cause reductions in the hippocampal circuit activity and a loss in synaptic plasticity (Effgen et al, 2014; Effgen et al, 2015; Vogel et al, 2015). Surprisingly, our data show very little dose response effect in the behavioral deficits that occur when the blast exposure is nearly doubled in magnitude.…”

Phosphodiesterase-4 inhibition restored hippocampal long term potentiation after primary blast

“…Long-term potentiation is the primary experimental model for investigating synaptic plasticity on a cellular level and is known to occur within the hippocampus (Bliss and Collingridge, 1993). It is well-documented that blast exposure in animals negatively affected hippocampal LTP, but this observation was not universal among preclinical models of blast TBI (Effgen et al, 2016; Goldstein et al, 2012; Huber et al, 2013; Vogel et al, 2016a; Yin et al, 2014). We have previously reported that 24 h post-injury, primary blast reduced the expression and phosphorylation of AMPA-GluR1 subunits (Vogel et al, 2016b), a key transmembrane receptor required for the induction and maintenance of LTP (Lee et al, 2000; Makino and Malinow, 2009; Mammen et al, 1997).…”

“…In comparison, our in vitro primary blast injury model isolates the shock wave component of blast from the other, confounding phases of injury (Effgen et al, 2012). The precisely controlled biomechanics of our injury model enables the study of neuronal dysfunction following primary blast injury in isolation (Effgen et al, 2012, 2016; Hue et al, 2014; Vogel et al, 2016b). …”