星形胶质细胞和神经损伤

星形胶质细胞的选择性调控

NIH Public AccessAuthor ManuscriptStroke. Author manuscript; available in PMC 2009 September 1.Published in final edited form as: Stroke. 2009 March; 40(3 Suppl): S8–12. doi:10.1161/STROKEAHA.108.533166.

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Astrocytes and ischemic injuryTakahiro Takano, NancyAnn Oberheim, Maria Luisa Cotrina, and Maiken Nedergaard Division of Glial Disease and Therapeutics. Center for Translational Neuromedicine. Department of Neurosurgery. University of Rochester Medical School. 601 Elmwood Avenue, Rochester, NY 14642

AbstractIschemic injury is traditionally viewed from an axiomatic perspective of neuronal loss. Yet the ischemic infarct encompasses all cell types, including astrocytes. This review will discuss the idea that astrocytes play a fundamental role in the pathogenesis of ischemic neuronal death. It is proposed that stroke injury is primarily a consequence of the failure of astrocytes to support the essential metabolic needs of neurons. This‘gliocentric view’ of stroke injury predicts that pharmacological interventions specifically targeting neurons are unlikely to succeed, because it is not feasible to preserve neuronal viability in an environment that fails to meet essential metabolic requirements. Neuroprotective efforts targeting the functional integrity of astrocytes may constitute a superior strategy for future neuroprotection.

IntroductionOver the past decade, a virtual revolution has occurred in our understanding of the physiology of astrocytes, and of their interactions with neurons in the normal brain 1, 2. For example, astrocytes actively propagate Ca2+ signals to neighboring neurons, whose level of synaptic activity they can actively modulate 3, 4. Key mediators of astrocyte-neuron signaling are glutamate 5 and ATP/adenosine 6. While much current work is focused on the role of gliotransmitters in synaptic transmission, the potential harmful effects of glutamate/ATP release from astrocytes in the ischemic penumbra has not been defined. Also, astrocytes have recently been implicated in the local control of blood flow 7-9, but it is not established how ischemia affects the ability of astrocytes to modulate vascular tone. We will here critically evaluate astrocytes as a potential new therapeutic target in stroke. Although the contribution of astrocytes to the process of ischemic infarction has not been clearly defined, an abundance of data already suggests the importance of astrocytes in both the initiation and propagation of secondary ischemic injury. Pathology of focal stroke Focal ischemia, or prolonged occlusion of a cerebral vessel, initiates the process of ischemic infarction, in which all tissue elements are affected. Ischemic infarcts are sharply demarcated and the transition between the infarct and the surrounding tissue is frequently less than 100μm. All cell types, including neurons, astrocytes, and the vasculature are dead in a chronic infarct

, whereas cells in the per-infarct areas are preserved. No evidence for neuronal loss outside chronic infarcts has been identified in either human or rodent brain 10, 11. In contrast, transient artery occlusion is frequently associated with selective neuronal injury with little, if any loss of astrocytes 12. Functional recovery after prolonged or permanent artery occlusion

Correspondence should be addressed to: Maiken Nedergaard, Divison of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, E-mail: nedergaard@urmc.rochester.edu..

星形胶质细胞的选择性调控

is often poor, indicating that ischemic infarcts have a much worse prognosis than transient

ischemic attacks (TIA) associated with selective neuronal injury.

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NIH-PA Author ManuscriptSupportive functions of astrocytesAstrocytes are the principal housekeeping cells of the nervous system. Their main supportivetasks are to scavenge transmitters released during synaptic activity, control ion and waterhomeostasis, release neurotrophic factors, shuttle metabolite and waste products, and toparticipate in the formation of the blood-brain-barrier 13. Failure of any of these supportivefunctions of astrocytes will, either alone or in combination, constitute a threat for neuronalsurvival. In fact, the all-and-none pattern of ischemic infarction indicates that neurons are notcapable of surviving in the absence of astrocytes. Unfortunately, our current understanding ofhow ischemia affects basic astrocytic functions is incomplete 14. It has not been establishedto which degree astrocytic glutamate uptake is impaired in the ischemic penumbra. It istherefore not possible to predict whether impairment of astrocytic glutamate uptake contributesmore significantly to neuronal death, than for example a decrease in astrocytic K+ bufferingcapacity.Astrocytes Ca2+ oscillations and Ca2+ wavesA growing body of evidence has in the last decade documented that astrocytes are more thanthe supportive cells of CNS. Astrocytes express neurotransmitter receptors and respond toneuronal activity by increases in cytosolic Ca2+ 15. Astrocytes display two distinct types ofCa2+ signaling modalities: Ca2+ oscillations and propagating Ca2+ waves 16. Ca2+ oscillationsare repetitive monophasic increases in cytosolic Ca2+ limited to a single cell. Ca2+ oscillationscan be evoked by exposure to several different transmitters, including glutamate, GABA, andATP 17. They can also be triggered by removal of extracellular Ca2+, or by exposure of culturedastrocytes to hypoosmotic solutions 18. An extensive literature has documented that astrocyticCa2+ oscillations involves activation of PLA, IP3 production, and release of Ca2+ from

intracellular stores, rather than Ca2+ influx through membrane channels 17.

The second modality of astrocytic Ca2+ signaling, propagating Ca2+ waves, can be stimulated

by focal electrical stimulation, mechanical stimulation, lowering extracellular Ca2+ levels, or

by local application of transmitters (glutamate or ATP). High frequency neuronal spiking has

been shown to induce astrocytic Ca2+ waves in organotypic slices and in anesthetized mice

following sensory stimulation 19, 20. In general, Ca2+ waves propagate with a velocity of

around 8 20 μm/s and expand over a maximum radius of 100 to 300 μM, including 10 to 50

astrocytes per wave. Initially, it was proposed that propagation of Ca2+ waves was conducted

through the diffusion of IP3 and/or calcium through intercellular gap junctions 21. Using

pharmacologic approaches, it was demonstrated that an extracellular agent, ATP, was the actual

diffusible messenger 22. Similar studies have in parallel shown that ATP mediates Ca2+ waves

in several non-excitable cells, including epithelium, liver, heart, and osteoblasts (see Berridge

2000 48). Wave propagation is mediated by P2Y receptors, likely including multiple purinergic

receptor subtypes in astrocytes, including P2Y1, P2Y2, and P2Y4 23. Ca2+ waves can be

viewed as a pathway for amplification of astrocytic activation. When an astrocyte reaches a

certain level of activation, it will release ATP that in turn increases Ca2+ in its neighbors

resulting in a spatial expansion of astrocytic activation 49. Purinergic signaling plays important

roles in coordination and synchronization of astrocytic responses to synaptic transmission.

Accordingly, inhibition of astrocytic P2Y receptors reduced and delayed Ca2+ increases in

cortical astrocytes following whisker stimulation 20. Little is known with regard to the effect

of ischemia on purinergic signaling. However, traumatic spinal cord injury is associated with

prolonged increases in astrocytic ATP release. Motor neurons express multiple purinergic

receptors, including P2×7 receptors. Administration of P2×7 receptor antagonists reduces

星形胶质细胞的选择性调控

tissue injury and improves functional recovery suggesting that excessive purinergic signaling

contributes to secondary damage following spinal cord injury 24.

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NIH-PA Author ManuscriptMechanisms of ATP releasePurinergic signaling represents the most important pathway by which astrocytes communicatewith other cells in CNS. A key step to understand the modulation of astrocytic function istherefore to define the mechanism by which these electrically unexcitable cells release ATP.Several pathways of ATP release have been proposed, including channel-mediated release,exocytosis of ATP containing vesicles, connexin (C×) hemichannels, and P2×7 receptorhemichannels, possibly linked to pannexins (reviewed in 25. Several observations indicate thatC×-hemichannels are the most significant mechanism of ATP release from astrocytes. It hasbeen shown that: C×-deficient glia cell lines increased ATP release 3 to 10-fold aftertransfection with C×43 22; C×-channel blockers (NPPB and FFA) potently inhibited ATPrelease 26; and single channel recordings indicate that ATP can exit through C×43hemichannels 27. Cultured neurons do not release ATP in response to K+ or receptor activation,suggesting that release of ATP from synaptic vesicles is low 28. Although neurons express thegap junction protein, C×36 29., this connexin has a small single channel conductance and isimpermeable to larger molecules, including Lucifer yellow and ATP 30. Astrocytes can releasemany other transmitters, including PGE2, glutamate, TNF-α, and d-serine, which play a rolein paracrine signaling between astrocytes and neurons, endothelial cells, and microglial cells.The pathways for release of these gliotransmitters have not been established. Nevertheless,excessive release of gliotransmitters in the setting of ischemia is likely contributing toadditional cellular damage, similar to the observations of increased ATP release in spinal cordinury.Astrocytic Ca2+ signaling as an integral part of brain functionPurinergic signaling represents the primary pathway for astrocyte-astrocyte signaling.

Emerging evidence indicates that astrocytes also modulate the function of other cell types in

brain by release of ATP and other gliotransmitters including glutamate, PGE2, and d-serine.

Several methods by which astrocytes modulate brain function are described here:

Synaptic transmission—A flurry of studies has over the past few years documented that

astrocytes can modulate neuronal Ca2+ levels and synaptic transmission by means of Ca2+

signaling. For example, spontaneous astrocytic Ca2+ oscillations and subsequent glutamate

release can drive NMDA-receptor-mediated neuronal excitation in the rat ventrobasal thalamus31, and astrocytes can potentiate inhibitory transmission in the hippocampus through a pathway

that is sensitive to kainate-receptor antagonists 32. These and other studies have pointed to

glutamate and ATP/adenosine as key mediators of astrocyte-to-neuron signaling 33. Astrocytic

release of ATP leads to the production of adenosine in the extracellular space by the action of

highly expressed nucleotidases that degrade ATP with a rapid time constant (～200 ms) 34.

Adenosine then acts as is a potent neurotransmitter, with pervasive and generally inhibitory

effects on neuronal activity 34. Several recent lines of work have demonstrated that astrocytes

can control network activity in both cortex and hippocampus through adenosine resulting from

astrocytic ATP release 28, 35. Adenosine has both presynaptic and postsynaptic effects.

Presynaptically, adenosine A1 receptors inhibited Ca2+ channel opening resulting in reduced

transmitter release, whereas postsynaptically, A1 receptors opened K+ channels resulting in

hyperpolarization and decreased neuronal activity 34. In a resting state, low levels of

extracellular adenosine tonically dampened neural activity, and the A1 receptor antagonist,

DPCPX, increased spontaneous cortical activity. Conversely, adenosine or the A1 specific

agonist CCPA potently suppressed local activity 34. Interestingly, adenosine and ATP have

recently been implicated in the depression of synaptic activity associated with increased

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.

星形胶质细胞的选择性调控

CONCLUSION

During evolution, neurons have lost many essential metabolic pathways as they became

increasingly specialized and gained the ability to generate action potentials and communicate

by synaptic transmission. As a consequence, neurons in the adult brain depend on metabolic

support from surrounding astrocytes. For example, neurons do not express the mitochondrial

enzyme glutamine dehydrogenase and cannot produce the chief excitatory transmitter,

glutamate, which in the adult CNS mediates 70% of neurotransmission. Since glutamate does

not pass through the blood-brain-barrier, excitatory transmission heavily depends on glutamate

produced by astrocytes 33. Similarly, synapse formation requires multiple lipids, including

cholesterol, produced by astrocytes 47. It is clear that neuron survival in both the normal and

the diseased brain relies heavily on surrounding astrocytes. A striking example is ischemic

infarcts, in which neurons do not survive if neighboring astrocytes are lost. While large gaps

exist with regard to our understanding of how ischemia affects the supportive function of

astrocytes, it is likely that failure of glutamate uptake, K+ buffering, water homeostasis,

vascular control, etc, all contribute to the massive loss of neurons in focal stroke. A challenge

for the future is to develop experimental tools to manipulate and monitor dynamic changes in

the supportive function in ischemic astrocytes.NIH-PA Author Manuscript

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NIH-PA Author ManuscriptFig. 1.

Ca2+ oscillations and Ca2+ waves represent two different modalities of astrocytic Ca2+signaling

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NIH-PA Author ManuscriptFig. 2.

ATP is the main transmitter by which astrocytes communicate with neighboring astrocytes.ATP is also an important paracrine transmitter in signaling to neurons, vessels, and microglialcells. Other gliotransmitters include glutamate, d-serine, and prostaglandins,

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