星形胶质细胞和神经损伤(3)

星形胶质细胞的选择性调控

concentrations of CO2 36, and one report found that extracellular ATP was increased in rat

striatum following MCA occlusion 37.

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NIH-PA Author ManuscriptControl of local microcirculation—Given that cerebral microvessels are extensivelyensheathed by astrocyte processes, thereby physically linking the intraparenchymal vasculaturewith synapses, it is tempting to speculate that astrocytes are involved in activity-inducedhyperemia 38, 39. Several studies suggest that astrocytes participate in activity-dependentparenchymal blood flow regulation. One study demonstrated that astrocytic activity caninfluence vascular tone, by observing that direct stimulation of perivascular astrocytes incortical slices caused vasodilation 7. It was demonstrated that mGluRs on astrocytes wereactivated by synaptic release of glutamate and that the resultant astrocytic Ca2+ signaling waslinked to changes in vascular diameter. This study concluded that a cyclooxygenase productwas involved, since acetylsalicylic acid blocked astrocyte-mediated vasodilation 7. Asubsequent study, which selectively targeted astrocytes by Ca2+ photolysis, found thatastrocytic Ca2+ signaling triggered cerebrovascular constriction 40. Similar to the first report,arachodonic acid (AA) metabolites were generated in astrocytes, but were proposed to diffuseinto smooth muscle cells, where they are converted to 20-HETE, a potent vasoconstrictor 40.The two papers raised considerable interest and it was speculated that use of L-NAME ordifferences with regard to brain regions (cortex versus hippocampus) could explain theopposing results. Importantly, both studies were performed in non-blood perfused brain slices,which has obvious limitations when studying functional hyperemia. Using 2-photon imagingof intact cortex in live adult mice, it was later demonstrated that photolysis of caged Ca2+ inastrocytic endfeet invariably triggered vasodilation 8. Astrocytic activation lead to an 18%increase in arterial cross-sectional area corresponding to an almost 40% increase in localperfusion. A specific COX-1 inhibitor (NS-398), as well as indomethacin, attenuated astrocyte-induced vasodilation. Furthermore, COX-1 immunoreactivity was strongly expressed aroundpenetrating cortical arteries, suggesting that COX-1 vasoactive products mediated vasodilation8. Recent work has supported the concept that COX-1 is the primary mediator of vasodilation

involving astrocytes 41.

Microglial cell activation—Recent reports using 2-photon imaging have shown that

astrocytes release ATP in response to local injury, this, in turn, activated local microglial cells42, 43. Microglial P2Y12 and P2Y6 receptors are critical for movement and phagocytosis,

respectively 44, 45. Together, these reports highlight the importance of astrocytic ATP release

and position purinergic signaling in as an important initial step of inflammatory responses.

Human astrocytes are more are larger, more complex, and more diverse than rodent

astrocytes

The relative ratio of glial cells to neurons increases algorithmically with phylogeny, manifestly

as a function of increasingly complex information processing 6. The human brain also contains

subtypes of GFAP positive astrocytes that are both human and primate specific, suggesting

their importance in the evolution of the human brain 46 . Additionally, human protoplasmic

astrocytes are significantly larger in diameter and more complex that the rodent counterpart

represented by a 2.5 fold increase in diameter and 10-fold more main GFAP positive processes.

Human protoplasmic astrocytes are organized into domains in which there is little overlap

adjacent cells processes, resulting in autonomous territories of neuropil that are influenced by

a single astrocyte. The domain of a single human astrocyte has been estimated to contain up 2

million synapses as well as vasculature, significantly greater than the estimated 20,000 to

120,000 synapses in rodent astrocytic domains 46. Therefore, human astrocytes can integrate

a larger contiguous set of synapses in conjunction with the vasculature creating a larger

glioneuronal unit linking neuronal activity with blood flow. Therefore, in adult humans then,

stroke may be more a disease of astrocytes than in our experimental rodent models.