Regional Changes in Interstitial K⁺ and Ca²⁺ Levels following Cortical Compression Contusion Trauma in Rats

Abstract

Brain trauma is associated with acute functional impairment and neuronal injury. At present, it is unclear to what extent disturbances in ion homeostasis are involved in these changes. We used ion-selective microelectrodes to register interstitial potassium ([K+]e) and calcium ([Ca2+]e) concentrations in the brain cortex following cerebral compression contusion in the rat. The trauma was produced by dropping a 21 g weight from a height of 35 cm onto a piston that compressed the cortex 1.5 mm. Ion measurements were made in two different locations of the contused region: in the perimeter, i.e., the shear stress zone (region A), and in the center (region B). The trauma resulted in an immediate increase in [K+]e from a control level of 3 mM to a level > 60 mM in both regions, and a concomitant negative shift in DC potential. In both regions, there was a simultaneous, dramatic decrease in [Ca2+]e from a baseline of 1.1 mM to 0.3-0.1 mM. Interstitial [K+] and the DC potential normalized within 3 min after trauma. In region B, [Ca2+]e recovered to near control levels within 5 min after ictus. In region A, however, recovery of [Ca2+]e was significantly slower, with a return to near baseline values within 50 min after trauma. The prolonged lowering of [Ca2+]e in region A was associated with an inability to propagate cortical spreading depression, suggesting a profound functional disturbance. Histologic evaluation 72 h after trauma revealed that neuronal injury was confined exclusively to region A. The results indicate that compression contusion trauma produces a transient membrane depolarization associated with a pronounced cellular release of K+ and a massive Ca2+ entry into the intracellular compartment. We suggest that the acute functional impairment and the subsequent neuronal injury in region A is caused by the prolonged disturbance of cellular calcium homeostasis mediated by leaky membranes exposed to shear stress.

P2X7Receptors Mediate ATP Release and Amplification of Astrocytic Intercellular Ca2+Signaling

“…Moreover, a recent study performed on two P2X 7 Ϫ/Ϫ mouse lines indicated that, at least in the hippocampus of healthy mouse brains, these receptors are either not expressed or are expressed at undetectable levels (Sim et al, 2004), suggesting that they are unlikely candidates for gliotransmitter release under physiological situations. In contrast, under pathological conditions such as during inflammation, ischemia, spreading depression, and trauma, when upregulation of these receptors, changes in extracellular cation composition, and increased extracellular ATP levels have been reported (Kraig and Nicholson, 1978;Harris and Symon, 1984;Nilsson et al, 1993;Le Feuvre et al, 2002;Guerra et al, 2003;Narcisse et al, 2005), the participation of P2X 7 R might be expected to exacerbate the extent of cell damage. Indeed, evidence for the participation of P2X 7 R in the regulation of extracellular transmitter levels was provided from studies showing that ATP-evoked glutamate efflux from neuronal and non-neuronal cells was greatly attenuated in P2X 7 R-null hippocampal slices (Papp et al, 2004) and from those showing that P2X 7 R antagonists greatly attenuated the extent of cell damage after acute spinal cord traumatic injury (Wang et al, 2004).…”

Regional Induction of c-Fosand Heat Shock Protein-72 mRNA following Fluid-Percussion Brain Injury in the Rat

“…In both cases, the authors suggest that a primary cause for lEG induc tion was calcium entry into cells resulting from cor- tical spreading depression (CSD). The occurrence of CSD, based on direct simultaneous measure ments of interstitial K + and Ca2 + and DC potential, has been reported following fluid-percussion injury (Sunami et al, 1989) and in a weight drop model of concussive brain injury (Nilsson et al, 1993). CSD could, in part, result in induction of c-fos in the thalamus and hippocampus via activation of corti cothalamic and entorhinal cortex-dentate gyrus projections, respectively.…”

Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca 2+ regulation of neuronal excitability

“…Normal and pathophysiological electrical activity can result in modest to substantial reductions (to <0.1 mM) in [Ca 2+ ] o in the interstitium and synaptic clefts in the brain, even following a single presynaptic action potential (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), well within the range of CALHM1 activation determined here. Profound reductions of [Ca 2+ ] o have been observed in spreading depression, anoxia, seizures, and traumatic injury that cause massive release of glutamate and activation of postsynaptic Ca 2+ influx pathways (10,(27)(28)(29)(30). Decreases in [Ca 2+ ] o have been observed to increase electrical excitability in various physiological and pathophysiological settings (21, 31, 32), but the mechanisms are not fully understood or accounted for.…”