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Astrocytes have traditionally been viewed as passive supportive cells, which were primarily responsible for maintaining an optimal environment for electrical neuronal activity. Recent studies have, however, demonstrated that the activity of nerve cells can be modulated by astrocytes, in that neurons are recruited into astrocyte-initiated and propagated calcium waves, both in vitro and in situ. By this means, propagated shifts in cytosolic calcium within the astrocytic syncytium may regulate neuronal response and firing thresholds. In turn, astrocytes are actively modulated by neuronal activity, and the existence of astrocyte–neuron signaling loops has been established in several areas of the brain. As a result of these findings, it is now recognized that astrocytes play an active role in brain function, particularly within the highly coupled astrocytic syncytium of the neocortex and the hippocampus. The mechanisms by which calcium signaling is propagated and how it is evoked are the focus of intense research activity. It is known that gap junctions and the connexins, their constituent proteins, together with the local cytoskeleton, the calcium buffer capacity, and calcium waves triggered by purinergic transmitters, all cooperate to modulate astrocytic signaling to neighboring cells in young animals. What changes do astrocytes and their signaling machinery undergo during the aging process? This is a question of paramount importance; altered astrocytic dynamics in the aged brain may alter synaptic efficacy and neuronal survival and perhaps contribute to the cognitive decline observed during aging. In this review, we analyze our current understanding of astrocytic function during aging by reexamining the mechanisms by which astrocytes contribute to neuronal function and survival in normal brain and the changes they undergo in the aged brain.

HOW DO ASTROCYTES AFFECT NEURONAL FUNCTION IN NORMAL BRAIN?

  1. Top of page
  2. HOW DO ASTROCYTES AFFECT NEURONAL FUNCTION IN NORMAL BRAIN?
  3. ASTROCYTES AS ACTIVE PARTICIPANTS IN SYNAPTIC TRANSMISSION
  4. ASTROCYTES IN THE AGING BRAIN
  5. DO AGED ASTROCYTES ALTER NEURONAL FUNCTION?
  6. ARE THE CHANGES IN AGED ASTROCYTES REVERSIBLE?
  7. CONCLUSIONS
  8. REFERENCES

Astrocytes outnumber neurons by five- to tenfold in the adult brain (Bignami, 1991) and establish numerous small contacts with neurons, neighboring astrocytes, and all the other brain cell types, including the endothelial cells of blood vessels (Rohlman and Wolf, 1996). These physical interactions allow them to function as metabolic and passive supportive cells of the brain. First, astrocytes regulate the ionic environment, in particular, after intense synaptic activity where unbalanced ionic fluxes, especially of K+ ions, are built up in the extracellular space (Karwoski et al., 1989). Second, astrocytic end feet contacts with capillaries and arterioles contribute to the blood–brain barrier formation (Janzer and Raff, 1987) and regulate blood flow after local changes resulting from neuronal activity (Clark and Mobbs, 1992). Third, astrocytes respond to the metabolic needs of neurons by activating glycogen metabolism and releasing lactate for neural consumption (Poitry-Yamate et al., 1995). Astrocytes can also respond to neuronal activity by clearance of glutamate from the extracellular space. Specific astrocytic glutamate transporters that are predominantly coupled to Na+-dependent systems mediate astrocytic glutamate uptake (for review see Anderson and Swanson, 2000). Once it is taken up by astrocytes, glutamate is either transformed into glutamine or oxidized via the tricarboxylic acid cycle (Martinez-Hernandez et al., 1977; Yu et al., 1982). Both pathways will lead to the production of several intermediates that will be taken up again by neurons as energy substrates (Poitry et al., 2000). Finally, glutamate–glutamine cycles between astrocytes and neurons are associated with intercellular fluxes of ammonium and constitute the major route for nitrogen balance between astrocytes and neurons (Marcaggi and Coles, 2001; Fig. 1).

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Figure 1. Metabolic coupling between neurons and astrocytes. Glutamate released from neurons at sites of synaptic activity is taken up by astrocytes via an Na2+-dependent transporter that is coupled to the Na2+/K+ ATPase (1). Glutamate in astrocytes is either converted to glutamine or oxidized in the tricarboxylic acid cycle (2). Glutamine is released by astrocytes and taken up by neurons, where it is converted back to glutamate to complete the cycle (3). This glutamate/glutamine cycle (4) also constitutes a major pathway for the flux of ammonium between the two cell types (5).

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ASTROCYTES AS ACTIVE PARTICIPANTS IN SYNAPTIC TRANSMISSION

  1. Top of page
  2. HOW DO ASTROCYTES AFFECT NEURONAL FUNCTION IN NORMAL BRAIN?
  3. ASTROCYTES AS ACTIVE PARTICIPANTS IN SYNAPTIC TRANSMISSION
  4. ASTROCYTES IN THE AGING BRAIN
  5. DO AGED ASTROCYTES ALTER NEURONAL FUNCTION?
  6. ARE THE CHANGES IN AGED ASTROCYTES REVERSIBLE?
  7. CONCLUSIONS
  8. REFERENCES

Although not electrically excitable, astrocytes express a variety of ion channels and neurotransmitter receptors by which they actively respond to neuronal activity (Porter and McCarthy, 1997; Newman and Zahs, 1998). In addition, astrocytes can release a variety of modulatory substances, including neurotransmitters [adenosine triphosphate (ATP), glutamate], growth factors [nerve growth factor (NGF), neurotrophin-3 NT-3), basic fibroblast growth factor (bFGF)], and cytokines (ICAM), to which neurons respond (Frohman et al., 1989; Dani et al., 1992; Condorelli et al., 1995; Kuzis et al., 1995; Araque et al., 1998). Thus, although brain function has been traditionally thought of in terms of neuronal activity, glial cells can also generate signals that affect their neuronal counterparts (Fig. 2). As a result, astrocytes have gained serious consideration as active modulators of brain function (Smith, 1994). One of the mechanisms by which astrocytes can signal to neighboring cells is by propagating calcium increments that spread from cell to cell. These calcium waves can travel over long distances within a population of astrocytes and alter the calcium levels of neurons, microglia (Nedergaard, 1994; Parpura et al., 1994), and endothelial cells (Leybaert et al., 1998).

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Figure 2. A,B: Astrocytic calcium waves trigger neuronal calcium increases. Electrical or mechanical stimulation of astrocytes to increase their calcium levels causes concomitant calcium increses in adjacent neurons.

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Astrocytic calcium waves propagation requires the presence of gap junction proteins (Finkbeiner, 1992; Charles et al., 1992; Blomstrand et al., 1999). Gap junctions are intercellular channels that connect the interior of two neighboring cells and serve as direct conduits of ions and small signaling molecules up to 1 kDa in size (Sáez et al., 1986). They are a particular feature of adult astrocytes, with more than 50,000 gap junction channels interconnecting each astrocyte to its neighbors (Yamamoto et al., 1990), in contrast to neurons and other brain cells, which are poorly coupled. Connexin 43 (Cx43) is the major, although not the only, gap junction protein found in astrocytes (Dermietzel and Spray, 1998). Astrocytic gap junctions help to distribute metabolic substrates and products within the brain (Tabernero et al., 1996), help to redistribute potassium ions after neuronal electrical activity (Ransom, 1996), and contribute to the so-called cell-to-cell communication via calcium waves mentioned above (Smith, 1994). However, recent studies have shown that astrocytic connexins serve other roles that do not necessarily require the formation of gap junction channels, such as the regulation of cytoskeletal organization (Cotrina et al., 2000) and of ATP release from glia (Cotrina et al., 1998). ATP can serve as a neurotransmitter in brain and activates responses in both neurons (Edwards et al., 1992; Gu and McDermott, 1997) and glial cells (Salter and Hicks, 1994) via either ligand-gated cation channels or metabotropic receptors that promote release of calcium from intracellular stores by the activation of the inositol triphosphate (IP3) signaling cascade (Kastrikis et al., 1992; Salter and Hicks, 1994). In addition, ATP and its related metabolites have important trophic effects on several brain cell populations by regulating neurite outgrowth (Neary et al., 1996), astrocytic shape changes (Neary et al., 1994; Rathbone et al., 1998), or survival of motor neurons via intracellular elevation of cyclic adenosine monophosphate (cAMP; Hanson et al., 1998).

The phenomenon of intercellular calcium signaling constitutes the foundation for the capacity of astrocytes to influence brain activity. For instance, direct stimulation of astrocytes can modulate the firing frequency of both inhibitory and excitatory neurons in dissected eyecup retinas (Newman and Zahs, 1998) and hippocampal cultures (Araque et al., 1998), and it can potentiate inhibitory synaptic transmission in hippocampal slices (Kang et al., 1998; Fig. 3). In addition, intracellular calcium oscillations in astrocytes can influence calcium dynamics of adjacent neurons (Pasti et al., 1997). Significantly, neurons can also affect the calcium levels of astrocytes in a reciprocal manner by the release of glutamate (Dani et al., 1992; Araque et al., 1998) or γ-aminobutyric acid (GABA; Kang et al., 1998). Thus, astrocytes and neurons establish feedback signaling loops that can affect a wide variety of synapses in the nervous system.

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Figure 3. Astrocyte stimulation modulates synaptic transmission in hippocampal slices. A: A pyramidal neuron (Pyr) exhibits an increase in miniature inhibitory postsynaptic currents (mIPSCs) after astrocyte (Ast) stimulation in hippocampus. B: Stimulation of a single astrocyte in a hippocampal slice loaded with the calcium indicator Fluo-3 triggers a calcium wave. BAPTA loading of the stimulated astrocyte (Ast) blocks the increase in mIPSCs of an adjacent pyramidal neuron (Pyr). The lower traces indicate five recordings before and after stimulation of a single astroyte.

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Grosche et al. (1999) have recently shown that small compartments of cerebellar glial processes appear to function as independent domains upon activation of neuronal inputs. Calcium increments in response to neuronal stimulation remained localized, and no spread of calcium signals within or between glial cells was observed. These observations call into question the existence of long-range calcium waves in the intact brain but provide evidence for the signaling importance of the spatial arrangement between neurons and astrocytes.

ASTROCYTES IN THE AGING BRAIN

  1. Top of page
  2. HOW DO ASTROCYTES AFFECT NEURONAL FUNCTION IN NORMAL BRAIN?
  3. ASTROCYTES AS ACTIVE PARTICIPANTS IN SYNAPTIC TRANSMISSION
  4. ASTROCYTES IN THE AGING BRAIN
  5. DO AGED ASTROCYTES ALTER NEURONAL FUNCTION?
  6. ARE THE CHANGES IN AGED ASTROCYTES REVERSIBLE?
  7. CONCLUSIONS
  8. REFERENCES

Astrocytes, in conjunction with microglia, respond profoundly to neuronal injury and undergo a series of metabolic and morphological changes that are known as reactive gliosis or astrogliosis (also observed under a variety of conditions, including cerebral ischemia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis; Schipper, 1996). Increased numbers of activated microglia and enlarged and phagocytic cells that express the cytokine interleukin-1 (IL-1) are prominent in reactive gliosis (Mrak et al., 1997). Concomitantly with the proliferation of microglial cells, there is hypertrophy of astrocytes and a marked variation in the expression of cytoplasmic antigens [glial fibrillary acidic protein (GFAP) and vimentin], surface proteins (PSA-NCAM), and growth factors (CNTF; Ridet et al., 1997). Metabolically, reactive astrocytes also exhibit an increase in oxidoreductive enzyme activities (Eddleston and Mucke, 1993). An early stage of reactive gliosis is what characterizes the astrocytes of the aging brain, even when no sign of disease is apparent. Aged astrocytes exhibit an elevated content of GFAP and of the calcium binding protein S100β (Sheng et al., 1996; Nichols, 1999). GFAP is not only increased at the single cell level but it is also detected in a higher proportion of total brain cells, suggesting that aging is associated with an increase in the relative number of glial cells. It has been estimated that the number of astrocytes and pericytes increases 20% in the aged cortex and other brain regions (Pilegaard and Ladefoged, 1996; Peinado et al., 1998; Rozovsky et al., 1998), whereas the number of oligodendrocytes and microglia does not change.

Use of oligonucleotide arrays has yielded the first profile of gene expression from the aging brain of mice and evidence that aging seems to be associated with an inflammatory response and oxidative stress both in neocortex and in cerebellum (Lee et al., 2000), with parallels to human neurodegenerative disorders. GFAP is also one of the genes that undergoes a twofold increase in expression. Thus, the GFAP increases of the aged astrocytes may be the result of a response to the inflammatory and oxidative state of the aging brain. Indeed, better comprehension of the features that distinguish a normal, “healthy” old brain from a brain that is at an early stage of a neurodegenerative disease is a key aspect in developing treatments. This is important because inflammatory and oxidative responses do promote alterations in calcium signaling (for review see Squier and Bigelow, 2000), which is the primary signaling mechanism by which astrocytes modulate neuronal function and could thus be critical for the progression from the “aged” to the “diseased” brain.

DO AGED ASTROCYTES ALTER NEURONAL FUNCTION?

  1. Top of page
  2. HOW DO ASTROCYTES AFFECT NEURONAL FUNCTION IN NORMAL BRAIN?
  3. ASTROCYTES AS ACTIVE PARTICIPANTS IN SYNAPTIC TRANSMISSION
  4. ASTROCYTES IN THE AGING BRAIN
  5. DO AGED ASTROCYTES ALTER NEURONAL FUNCTION?
  6. ARE THE CHANGES IN AGED ASTROCYTES REVERSIBLE?
  7. CONCLUSIONS
  8. REFERENCES

To our knowledge, alterations in the calcium regulation and activity of aged astrocytes remain totally unexplored. It has been shown only very recently that aged astrocytes continue to express high levels of gap junction proteins and, more importantly, that these gap junction channels are functional (Cotrina et al., 2001; Fig. 4). However, connexin-mediated calcium signaling among aged astrocytes and surrounding cells has not been evaluated. Likewise, cytoskeletal changes of aged astrocytes that could affect calcium signaling have not been reported. As mentioned above, the metabolic turnover of GFAP is increased in aged glia (Amenta et al., 1998), and accumulations of tau, although not neurofibrillary tangles (NFT), have been found in astrocytes and oligodendrocytes of aged baboons (Schultz et al., 2000). Glial tangles also contain hyperphosphorylated tau, as do NFT present in neurodegenerative neurons, but most of the proteins associated with NFT are absent (Ikeda et al., 1998). Therefore, glial tangles can be considered an earlier stage of the tangles observed in neurodegenerative disease. Alterations in cytosolic calcium can increase tau hyperphosphorylation (Mattson et al., 1991). However, at present we do not know how these changes might affect glial calcium signaling. Finally, nothing is known about the activity of extracellular purinergic compounds in glia of the aged brain. Measurements in cell suspensions of aged mouse cortex demonstrate alterations in intracellular ATP maintenance (Joo et al., 1999), which could be translated as changes in the production of extracellular ATP and its derived metabolites. Importantly, adenosine levels are increased under pathological conditions, including ischemia and epileptic activity (Phillis et al., 1991; Rudolphi et al., 1992). It has been hypothesized that, under these circumstances, purines may play a neuroprotective role by enhancing neuronal survival and decreasing excitotoxic transmitter release. Indeed, clinical trials with synthetic purine derivatives are currently being undertaken in patients with Alzheimer's disease (Rathbone et al., 1999). However, the actual adenosine levels in the aged brain are totally unknown.

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Figure 4. Functionality of astrocytic gap junction proteins is preserved in the aged brain. The fluorescence recovery after the photobleaching technique (FRAP) allows monitoring of gap junction function in vivo: hippocampal slices from 3-month-old (left) and 21-month-old (right) mice are loaded with the gap junction-permeable tracer CDCF (top panels); an area is selected for laser bleaching (rectangle; middle panels); refill of fluorescence is recorded 2 min after laser bleach (bottom panels).

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Another aspect that can contribute to altered generation of cellular ATP is the redox condition of the aged astrocytes. As mentioned above, alterations in oxidation and stress proteins seem to be a common feature of the aged brain and are likely to affect the calcium homeostasis and the generation of extracellular ATP. For instance, IL-1, a cytokine produced by activated microglia, induces S100β expression in astrocytes, which, in turn, increases intracellular free calcium levels (Mrak et al., 1995). IL-1 can differentially regulate calcium wave propagation by switching between a gap junction-mediated event to a purinergic-mediated pathway (John et al., 1999). Oxidation in the calcium signaling protein calmodulin (CaM) alters the maintenance of intracellular calcium levels and changes the transport activity of the plasma membrane Ca-ATPase of aged muscle and neuronal cells (Squier and Bigelow, 2000). Oxidation of the thiol groups in the IP3 receptor will lower the threshold IP3 concentration for calcium release (Peuchen et al., 1996), promoting amplified calcium responses (Fig. 5).

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Figure 5. Schematic representation of interastrocytic calcium signaling and some of the alterations that oxidation can induce in calcium regulatory elements of the cascade. When an astrocyte is activated, inositol phosphate is produced via PLC (I). The triggering of an IP3-dependent cascade promotes calcium release from intracellular stores to the cytoplasm (II). The calcium signal is then propagated to neighboring cells by two possible mechanisms: the diffusion of IP3 through gap junction intercellular channels (IIIa) and/or a calcium-dependent pathway that activates ATP release to the extracellular media (IIIb). ATP in turn activates P2 purinergic receptors in the membrane of the nearby cells and amplifies the calcium signal.

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Several calcium regulatory proteins can be affected upon oxidation (indicated by asterisks in Fig. 5). Oxidation of the IP3 receptor can amplify calcium responses, whereas changes in the oxidation state of the calcium signaling protein Ca2+/calmodulin (Ca2+/CaM) can modify the activation state of the Ca2+-ATPases located in the plasma membrane.

All these changes are likely to affect not only the signaling capability of the astrocytes but also of all the other brain cells, including the neurons. Thus, on the basis of the tendency of the aging brain to exhibit inflammatory and oxidative signs, and the consequences for many metabolic and signaling proteins, we can expect that the resting calcium levels of aged astrocytes show an overall increase. This might be the turning point for subsequent changes in the calcium signaling capabilities of the aging astrocytes. For example, increased resting calcium levels would tend to enhance the calcium signaling capability by lowering the threshold for IP3 release. However, alterations in the ATP maintenance caused by aging will change the ratio of ATP and its derivatives in the extracellular space (for example, by increasing the rate of transformation from ATP into adenosine). Although adenosine can promote neuronal survival (see above), it might also reduce ATP signaling activity, a key component for calcium wave propagation. Thus, on the one hand, calcium signaling in the aging brain could be enhanced as a result of an increase in resting calcium levels of astrocytes, but, on the other, ATP-mediated activity might be reduced, but compensated for in part, by an increase in gap junction-mediated calcium waves promoted by IL-2 and other inflammation-related molecules. How will these properties impact the activity and survival of the neighboring neurons? We do not know. It is imperative that we start filling the gaps in our knowledge of the modulatory role of astrocyte-mediated calcium signaling. First, we have to evaluate how a gap junction-mediated wave differs from a purinergic-mediated wave in its ability to affect nearby neurons and surrounding cells. Second, we have to measure the extracellular levels of ATP and its derivatives accurately so that we can appreciate the exact contribution of each to calcium signaling during the aging process. Third, and most important, we certainly have to study the persistence of calcium waves in the aging brain and the degree of signaling to neighboring cells. One possible way to answer all of these questions would be to establish an experimental model that keeps the astrocytic–neuronal circuitry intact. An option might be the use of intact brain slices obtained from adult and aging animals. The more physiologically relevant conditions that are attained with this approach would be ideal for beginning to address most of the questions posed above.

ARE THE CHANGES IN AGED ASTROCYTES REVERSIBLE?

  1. Top of page
  2. HOW DO ASTROCYTES AFFECT NEURONAL FUNCTION IN NORMAL BRAIN?
  3. ASTROCYTES AS ACTIVE PARTICIPANTS IN SYNAPTIC TRANSMISSION
  4. ASTROCYTES IN THE AGING BRAIN
  5. DO AGED ASTROCYTES ALTER NEURONAL FUNCTION?
  6. ARE THE CHANGES IN AGED ASTROCYTES REVERSIBLE?
  7. CONCLUSIONS
  8. REFERENCES

Human aging is associated with a number of pathologies that affect only brain tissue. Thus, any strategy that can boost the defense mechanisms in the brain could contribute to improved neuronal performance, specifically because normal aging is usually accompanied by diminished brain function, particularly in memory and cognition, but not by significant widespread neuronal death (Rasmussen et al., 1996; Rapp and Gallagher, 1996). Nonetheless, a recent report has described an extensive decline in the number and size of neurons in subcortical regions of aged monkeys (Smith et al., 1999). These nuclei project to hippocampal and neocortical areas (Mesulam et al., 1983), and, when they are altered, their dysfunction leads to deficits in attention and some aspects of memory (Wainer et al., 1993; Voytko et al., 1994). Importantly, the same study utilized nerve growth factor to reverse the effects of neuronal atrophy, suggesting that age-associated therapies might, indirectly, improve neuronal activity. In the same context, reversing some of the changes that astrocytes undergo during aging might, in theory, help the overall performance of the senescent neurons.

Increases in the GFAP content of astrocytes have not been ascribed any particular role other than the shape changes associated with the natural maturation process of this cell type. However, although we are not certain of how increased GFAP may alter astrocytic function, some mutations of this gene in mice are starting to reveal the consequences of altered GFAP in neuronal function. First, GFAP null astrocytes are a better substrate for neuronal survival and neurite outgrowth than wild-type astrocytes (Menet et al., 2000), which in part may explain why high levels of GFAP are achieved only relatively late in maturing astrocytes, when the peak of neurogenesis has already occurred. McCall et al. (1996) have reported that deletion of the GFAP gene in the mouse, which per se does not cause any obvious deleterious phenotype, promotes an increase in long-term potentiation, a widespread form of neuronal synaptic plasticity. Analysis of cerebellar circuits shows that long-term depression, another form of synaptic plasticity, is deficient in GFAP mutant mice, although motor coordination is normal (Shibuki et al., 1996). More dramatically, mice lacking GFAP are more sensitive to traumatic spinal cord injury (Nawashiro et al., 1998).

On the other hand, overexpression of human GFAP in astrocytes of transgenic mice provokes fatal encephalopathy (Messing et al., 1998). It is believed that GFAP accumulates in cytoplasmic inclusions similar to those observed in Rosenthal fibers that appear in Alexander's disease. Indeed, a recent report has associated mutations in GFAP with the etiology of this CNS disorder, which is characterized by seizures, psychomotor retardation, and juvenile death (Brenner et al., 2001). These observations suggest that the changes exhibited by activated astrocytes, together with the associated modifications in cell surface molecules and extracellular matrix (Ridet et al., 1997), are likely to be associated with alterations in astrocytic–neuronal interactions that affect synaptic activity and neuronal survival.

Is it possible to reverse the increase in the GFAP content of aged astrocytes? This might be the case. Caloric restriction, an intervention usually associated with increased longevity in rodents, worms, and yeast (Guarente and Kenyon, 2000), prevents by more than 50% the age-associated GFAP increase of old mice. At present, we do not know whether caloric restriction can be considered as a therapy for humans.

An alternative therapy to reverse some of the changes of aged astrocytes is hormonal intervention. Brain astrocytes are sensitive to the action of a variety of steroid hormones. Both astrocytes and oligodendrocytes express a variety of hormone receptors, particularly receptors for glucocorticoids, mineralocorticoids, and the sex hormones androgen, estrogen (ERα and -β), and progesterone (Melcangi et al., 1999). Activated steroid receptors regulate astrocytic expression of growth factors (Jurgen and Lehner, 1995), GFAP and glutamine synthetase (Juurlink et al., 1981; Laping et al., 1994; Rozovsky et al., 1995), proteins that regulate ion channel function (Yarowski et al., 1994; Bohn et al., 1994) and inhibit proliferation (Gould et al., 1992; Crossin et al., 1997). Estrogen has positive effects on calcium signaling; estrogen pretreatment of cultures of cortical astrocytes results in a severalfold increase in the extent of calcium wave propagation. In addition, two glucocorticoids, methylprednisolone and dexamethasone, are also potent stimulators of astrocytic calcium waves, altering both the resting calcium levels and the amplitude of calcium wave propagation (Simard et al., 1999; Fig. 6). Furthermore, ATP release is proportionally enhanced by steroid treatment, whereas the functional coupling and the expression of Cx43 remain unaltered in hormone-treated cultures (Simard et al., 1999). Thus, should astrocytic calcium signaling decline in the aging brain, we could use compounds that potentiate, rather than inhibit, interastrocytic calcium as agents intended to counteract age-related decline in astrocytic calcium signaling.

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Figure 6. A,B: Astrocytic calcium signaling can be up-regulated by hormone treatment. Hormone incubation of cultured astrocytes loaded with Fluo-3 shows enhanced astrocytic calcium signaling by increasing both the amplitude of the calcium responses and the extent of wave propagation.

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CONCLUSIONS

  1. Top of page
  2. HOW DO ASTROCYTES AFFECT NEURONAL FUNCTION IN NORMAL BRAIN?
  3. ASTROCYTES AS ACTIVE PARTICIPANTS IN SYNAPTIC TRANSMISSION
  4. ASTROCYTES IN THE AGING BRAIN
  5. DO AGED ASTROCYTES ALTER NEURONAL FUNCTION?
  6. ARE THE CHANGES IN AGED ASTROCYTES REVERSIBLE?
  7. CONCLUSIONS
  8. REFERENCES

From the studies described above, it is clear that our knowledge of the functional features of aged astrocytes is still very limited. We do not know whether aged astrocytes maintain their structural integrity as well as their signaling capabilities. We do not know how inflammation and oxidation change glial function and, consequently, modulate synaptic function. More importantly, no studies have been conducted to investigate whether the changes in aged astrocytes contribute to neurodegeneration. Finally, caution must be taken in hormonal therapies for the senescent brain; although estrogens seem to have a neuroprotective role against the onset of Alzheimer's disease (Morrison et al., 1997), prolonged presence of glucocorticoids favors instead memory deficits (Lupien et al., 1998). Clearly, future work is needed to address how the changes of aged astrocytes impair astrocytic performance with emphasis on studies performed in situ in the aged brain rather than in aged astrocytes cultured in vitro.

REFERENCES

  1. Top of page
  2. HOW DO ASTROCYTES AFFECT NEURONAL FUNCTION IN NORMAL BRAIN?
  3. ASTROCYTES AS ACTIVE PARTICIPANTS IN SYNAPTIC TRANSMISSION
  4. ASTROCYTES IN THE AGING BRAIN
  5. DO AGED ASTROCYTES ALTER NEURONAL FUNCTION?
  6. ARE THE CHANGES IN AGED ASTROCYTES REVERSIBLE?
  7. CONCLUSIONS
  8. REFERENCES