Abstract
Traumatic brain injury results in neuronal loss and associated neurological deficits. Although most research on the factors leading to trauma-induced damage focuses on synaptic or ionic mechanisms, the possible role of direct intercellular communication via gap junctions has remained unexplored. Gap junctions connect directly the cytoplasms of coupled cells; hence, they offer a way to propagate stress signals from cell to cell. We investigated the contribution of gap junctional communication (GJC) to cell death using an in vitro trauma model. The impact injury, induced by a weight dropped on the distal CA1 area of organotypic hippocampal slices, results in glutamate-dependent cell loss. The gap junctional blockers carbenoxolone and octanol decreased significantly post-traumatic cell death, measured by propidium iodide staining over a 72 hr period after the impact. Dye coupling in the pyramidal layers was enhanced immediately after the injury and decreased over the following 24 hr. To determine whether specific connexins were involved in the spread of trauma-induced cell death, we used organotypic slices from connexin43 (Cx43) knock-out mice, as well as acute knock-outs by incubation with antisense oligodeoxynucleotides. Simultaneous knockdown of two neuronal connexins resulted in significant neuroprotection. Slices from the null-mutant Cx43 mice, as well as the acute Cx43 knockdown, also showed decreased cell death after the impact. The gap junctional blockers alleviated the trauma-induced impairment of synaptic function as measured by electrophysiological field potential recordings. These results indicate that GJC enhances the cellular vulnerability to traumatic injury. Hence, specific gap junctions could be a novel target to reduce injury and secondary damage to the brain and maximize recovery from trauma.
Highlights
Traumatic brain injury results in neuronal loss and associated neurological deficits
We used an in vitro impact injury model, which has been described previously (Adamchik et al 2000). This traumatic injury, induced by a weight dropped from a standard height on the distal CA1 area, results in delayed progressive cell death, which is colocalized with the impact within first 24 hr and spreads throughout the entire slice over 48 –72 hr
In addition to the neuronal and glial loss, as determined by staining with the viability indicator propidium iodide (PI) or by cresyl violet-stained cell counts (Fig. 1 A), we observed an increase in glial fibrillary acidic protein (GFAP)-positive cells (Fig. 1 A), which may reflect the known phenomenon of proliferation of astrocytes, termed reactive gliosis, that occurs after traumatic episodes (D’Ambrosio et al, 1999)
Summary
Traumatic brain injury results in neuronal loss and associated neurological deficits. The gap junctional blockers alleviated the traumainduced impairment of synaptic function as measured by electrophysiological field potential recordings These results indicate that GJC enhances the cellular vulnerability to traumatic injury. Traumatic brain injury results in loss of neurons that have been mechanically damaged as well as other cells that, not directly damaged, are subjected to a delayed degeneration. This secondary brain damage is attributable to several pathogenic factors, including focal ischemia and ionic fluxes (Hovda et al, 1992; Siesjo, 1993), and is usually preventable. The evidence that we present indicates that GJC participates in the trauma-induced cell death
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