SID 26681509 br WM astrocytes Grey matter astrocytes express

WM astrocytes Grey matter astrocytes express a variety of GluR types that have both physiological and pathophysiological significance [87]. Non-NMDA GluR are also expressed in WM astrocytes [40], although the functionality of these receptors has not been tested. The fibrous astrocytes that populate WM are significantly more sensitive to acute ischemic injury than their protoplasmic GM counterparts [95], but there is currently no evidence that this is a related to GluR expression [31,91,111]. Astrocytes have long been promulgated as the principle source of intracellular glutamate released during ischemia. However, we have recently used biosensor electrodes to measure extracellular glutamate in real time during modelled ischemia and found no effect of blocking known pathways for astrocyte release in WM, at least in the initiate stages of injury [29]. This work indicates that the principle source of ischemic glutamate release in adult WM is the axon cylinder, as discussed below. Irrespective of cellular glutamate release pathways, injury to WM astrocytes that compromises the cell membrane must a priori liberate the intracellular glutamate within the SID 26681509 into the extracellular space [32]. This event may occur more quickly in WM due to the heightened ischemic-sensitivity of fibrous astrocytes. Imaging of transgenic mice expressing GFP under an astrocyte-specific promoter has been used to examine astrocyte injury during modelled ischemia. In neonatal WM this reveals a remarkable degree of variability in susceptibility to ischemic injury between astrocyte populations, with 82% of WM astrocytes in the P10 optic nerve dead 100 min after a 20 min ischemic insult compared to only 3% of hippocampal GM astrocytes [95]. Within a single population of astrocytes, the mechanisms underlying injury change dramatically with development, with P2 RON astrocytes dying following cytotoxic Ca2+-influx via VGCC activation [31] and P10 RON astrocytes dying via a form of acute cell swelling mediated by Na-K-Cl co-transport (NKCC) [111]. WM injury in a focal in vivo adult ischemia model was subsequently shown to be significantly NKCC-mediated [15]. In addition to cell lysis, loss of astrocyte processes during ischemia, termed clasmatodendrosis, may have profound consequences for neighbouring cellular elements and astrocyte function, and is mediated by a not fully understood non-NKCC-transporter dependent mechanism [91]. Evidence for a significant role for direct astrocyte pathology include studies showing selective WM astrocyte injury in neonatal spinal cord [58] and brain [11], where WM astrocyte loss in some structures was more significant than oligodendrocyte loss and was followed by astrocyte division. Hypoxia-ischemia in P7 rat induces clasmatodendrosis and cell death in WM astrocytes, with similar effects seen in post-mortem fetal and neonatal human brain [41]. It is therefore probable that liberation of intracellular glutamate from astrocytes will contribute significantly to an elevation in extracellular glutamate in WM at latter ischemic time points when astrocyte functional integrity becomes compromised.
WM astrocyte pH regulation may differ from that in GM: significance for GluRs Brain ischemia is associated with acidosis, a phenomenon that is critical in the injury process [16,71]. Recent developments in in vivo imaging indicate significant acidosis in WM during a model of stroke [67]. The transmission pathways linking acidosis with stroke injury may involve acid-sensing channels [116,118]; conversely, elevated [H+] may be protective against excitotoxic injury due to block of NMDA GluRs [108]. Recent evidence indicates that astrocyte acidosis can also evoke glutamate release capable of triggering the excitotoxic cascade implicated in many disease states [9]. Considering the importance of NMDA GluRs for WM injury in stroke, failure of pH regulation in WM during ischemia may be of particular clinical significance. Astrocytes are responsible for extracellular ion homeostasis in WM, including contributing to the regulation of H+ [16,86]. Cell culture studies using astrocytes report resting intracellular pH (pHi) levels in astrocytes of ∼7.2, and pHi values of 7.0 (peri-capillary astrocytes: [105]) and 7.04 (neocortical protoplasmic astrocytes [17]:) have been reported in situ. One report from retinal astrocytes identified on morphological criteria using fluorescent dye (AM-loaded) reported pHi of 7.27 [72]. The lack of definitive cell identification in these studies encouraged the use of neuron-depleted “gliotic” preparations that reported pHi values of 7.03–7.30 from reactive astrocytes loaded with the fluorescent dye BCECF [30,42,43], while gene-gun delivery to neonatal organotypic hippocampal slices of transgenic pH reporters has been used to measure a resting pHi of 7.28 [83]. Taken together these studies demonstrate the presence of Na-HCO3 cotransport (NBC) in adult retinal astrocytes [72], NBCe1 (SLC4A4) in juvenile cortical astrocytes [110], and NBC and Na-H exchange (NHE) in astrocytes in gliotic slices [30,42,43].