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uninjured control

Time Post-Injury

24 hrs.

influx, thereby further contributing to elevated in-tracellular calcium (Floyd et al., 2005). Mechanical strain injury causes release of ATP from damaged mitochondria (Ahmed et al., 2000; Neary et al., 2005), some of which is released into the extracellular space. Although the mechanism of ATP release after injury is still unknown, candidates for release include hemichannels, ATP transporters, or vesicular exocytosis (Schwiebert, 2001). Extracellular ATP following injury can activate pur-inergic receptors including the P2YRs. Activation of the P2YRs can increase intracellular calcium, and also can have beneficial effects such as activation of cytoprotective pathways and increased expression of Bcl-2 (Neary et al., 2003, 2005). Propidium iodide, a marker of cell damage and death, could enter the cell via perturbations in the cell membrane. As astrocytes are extensively coupled via gap junctions, small molecules such as Ca2+ and IP3 could travel between cells to potentially propagate an injury signal, as will be discussed below.

Work in uninjured astrocytes shows that gap junction communication is an important element in intercellular calcium signaling in astrocytes which facilitates intercellular transfer of ions (i.e., Ca2+ or Na+) or second messengers (i.e., IP3). Gap junctions are connections of intercellular channels formed by hemichannels from adjoining cell membranes, and the adult brain astrocytes are so abundantly interconnected that the network is regarded as a syncytium. Gap junctions are formed by the joining of 2 hemichannels, each of which comprises six protein subunits termed con-nexins. The connexin43 protein (Cx43) is highly expressed in astrocyte gap junctions while other connexin proteins comprise neuronal gap junctions (Yamamoto et al., 1990a, b; Giaume and McCarthy, 1996). Gap junctions are not simply passive channels between cells, but functionally respond to alterations in the cellular milieu that alters gap junction assembly and permeability, mainly via phosphorylation (Musil et al., 1990; Nagy and Li, 2000; Rouach et al., 2002; VanSlyke and Musil, 2005). Most studies of the effect of injury on gap junction coupling have used models of ischemic brain injury with divergent findings. Increases in intracellular calcium, decreases in pH, and production of oxygen-free radicals can inhibit gap junction coupling (Bolanos and Medina, 1996; Martinez and Saez, 2000); yet, other evidence suggests that gap junctions remain open during ischemia (Cotrina et al., 1998a). The role of gap junction communication in cell death following an ischemic insult is also unclear. Some groups report that inhibition of astrocyte gap junctions during ischemic injury decreases the area of infarct and is neuroprotective (Lin et al., 1998; Frantseva et al., 2002), suggesting that astrocyte gap junctions amplify damage and spread cell death signals to otherwise viable cells. An alternative hypothesis suggests that gap junctions enable astrocytes to use the syncytium to dissipate otherwise toxic concentrations of glutamate or ions (Blanc et al., 1998; Siushansian et al., 2001). Part of the controversy over the role of gap junction communication in ischemic injury may be related to heterogeneity in gap junction coupling as well as regional or cellular differences in intracellular regulation of gap junctions (Zvalova et al., 2004). For example, gap junction hemichannels that open to the extracellular space have been characterized (Contreras et al., 2002) and may be involved in calcium signaling or ATP release (Stout et al., 2002; Bennett et al., 2003; Dermietzel et al., 2003).

The effect of traumatic brain injury on astrocyte gap junction communication has only recently been investigated. Ohsumi et al. (2006) have shown that CX43 immunohistochemistry was increased in the hippocampus 24 and 72 h after lateral fluid percussion injury. We evaluated the effect of mechanical strain injury on functional connectivity of gap junctions in astrocytes. In this experiment, primary astrocyte cultures were grown on Flex® plates and subjected to either a mild or moderate rapid mechanical strain injury as previously described (Floyd et al., 2005). Gap junction coupling was evaluated at 30 min, 4h, or 24 h after mechanical strain injury using fluorescence recovery after photobleach (FRAP). Astrocytes were bath loaded with 0.05 mg/ml 5-(and 6-) car-boxyfluorescein diacetate-AM (CFDA) which is a cell membrane and gap junction permeable dye that becomes membrane impermeable after de-esterification. Thus, when cells are visualized, the CFDA is trapped within the cells but can transfer between coupled cells via gap junctions. After the fluorescent moieties of the dye are bleached by intense laser excitation in a cell, any subsequent increase in fluorescent intensity, or recovery, is attributed to transfer of dye between gap junctions and represents the extent of gap junction coupling. In this experiment, cells were visualized on an upright Zeiss Axioscop 2 Laser scanning confocal microscope (LSM510) using a Zeiss Achroplan 20 x dipping objective. The dye was excited at 400 nm with emitted fluorescence above 520 nm captured by a photo-multiplier tube. Two cells near the middle of the field were selected for bleach and regions of interest (ROIs) were drawn. Two additional ROIs were drawn for other cells in the field that were not subjected to photobleach. Three field scans were obtained prior to bleach. Selected cells were bleached with 100 iterations at 100% laser power. To assess recovery after bleach, field scans were acquired every 2 s for the next 2.5 min (75 scans total). Digital images obtained during experiments were saved on a PC for off-line analysis. Mean intensity values for each ROI were divided by mean intensity values of reference (non-bleached) cells to correct for photobleach of the entire field. Figure 2(A) shows representative micrographs of uninjured astrocytes (left column) and astrocyte subjected to a moderate mechanical strain injury (6.5 mm deformation) 30 min prior to FRAP analysis. The ROIs outlined in red and green were bleached but the ROIs outlined in yellow and blue were not. A representative trace of the percentage of fluorescence recovery over time for an astrocyte mildly injured 24 h prior to FRAP is shown in Fig. 2(B). Recovery of fluorescence is rapid and begins to plateau by ~400 s after bleach. Quantification of the maximal recovery at various post-injury times is shown in Fig. 2(C). Uninjured astrocytes were moderately coupled and recovery after photobleach was between 30 and 40%. Neurons are reportedly not extensively coupled and were used as a procedural control with less than 5% fluorescence recovery detected in adjacent neurons in co-cultures. In mildly injured as-trocytes, a significant increase in recovery after photobleach was seen at 30 min, and 4 and 24 h after mechanical strain injury. However, with moderate strain injury, recovery after photobleach was decreased at these same time-points. Recovery of photobleach was assessed after severe strain injury, but many severely injured cells leaked dye into the extracellular compartment, rendering the severe injury data inconclusive (data not shown). In summary, we found that mild injury increases functional coupling and moderate injury decreases coupling. Additional experiments will be conducted to better understand the mechanisms of these changes in gap junction coupling after mechanical strain injury and their role in the patho-physiology of traumatic brain injury.

Conclusion

With some notable exceptions such as the study of gliosis and astrocytic swelling, most TBI research has generally focused on the pathophysiology of neurons. However, many recent developments in the field of glial biology demonstrate the active nature of neuronal-astrocyte signaling indicating the vital importance of astrocytes in normal brain function. Furthermore, recent studies in Neuro-trauma demonstrate the vulnerability of astrocytes to CNS insults. Therefore, defining the time course of astrocyte damage after TBI and uncovering the mechanisms mediating that damage are critical to a more complete understanding of TBI patho-physiology. Collectively, these findings are leading to a novel departure from traditional approaches to TBI pathophysiology that have generally concentrated on injury to neurons.

Acknowledgments

Support provided by UCD Health Systems Research Award (CLF), NIH NS29995 (BGL), NIH NS45136 (BGL).

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