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Astrocytes are essential not only for keeping the highly differentiated neurons in their proper place within the brain, but also for maintaining their physiological environment (Lugaro 1907). It is known (Newman 1995) that a highly regulated intercellular environment is required for neuronal function and that astrocytes regulate the crucial environmental homeostasis of electrolytes, water, and pH and which eliminate amino acids and proteins from the extracellular space. Although primarily the role of endothelial tight junctions, astrocytes also uphold the blood-brain barrier (BBB) from extracerebral influences by controlling and regulating the intercellular transport of molecules from the vessel to the neuron.

Astrocytes perform the following functions: 1. Developmental function (neurotrophic action). Astrocytes are indispensable for neuronal survival, migration, and neurite outgrowth. GFAP-ne-gative astrocytes constitute a better substrate for such functions than GFAP-positive astrocytes. This phenomenon may explain why astrocytes do

Fig. 3.4a-h. Astrocytes. a, b White matter astrocytes, i.e., fi- tion X300); f anisomorphic gliosis (GFAP; magnification X300);

brous astrocytes (GFAP; magnification a X500; b Xl,000); c gray g Alzheimer type II astrocytes marked by arrows (H&E; magnifi-

matter astrocytes, i.e., protoplasmic astrocytes (GFAP; magnifica- cation Xl,000); h clasmatodendrosis of GFAP-positive astrocytes tion X300); d activated, plump (hypertrophic) astrocytes (GFAP; (GFAP; magnification Xl,000) magnification Xl,000); e isomorphic gliosis (GFAP; magnifica-

Fig. 3.4a-h. Astrocytes. a, b White matter astrocytes, i.e., fi- tion X300); f anisomorphic gliosis (GFAP; magnification X300);

brous astrocytes (GFAP; magnification a X500; b Xl,000); c gray g Alzheimer type II astrocytes marked by arrows (H&E; magnifi-

matter astrocytes, i.e., protoplasmic astrocytes (GFAP; magnifica- cation Xl,000); h clasmatodendrosis of GFAP-positive astrocytes tion X300); d activated, plump (hypertrophic) astrocytes (GFAP; (GFAP; magnification Xl,000) magnification Xl,000); e isomorphic gliosis (GFAP; magnifica-

not express GFAP until relatively late in CNS development after the early phase of neurogenesis has been completed (Menet et al. 2000). Astrocy-tes also promote myelin synthesis and remyelina-tion (Franklin et al. 1993).

2. Electrolyte and water homeostasis and osmoregulation. Depolarization of neurons is achieved by a cellular efflux of K+ from active neurons with a consequent increase in extracellular K+. Astro-cytes possess mechanisms for active and passive accumulation of K+ in the intercellular space and the transfer of K+ by spatial buffer currents to the capillaries and/or cerebrospinal fluid (CSF) space (Newman 1995). As stated above, astrocytes regulate not only K+ homeostasis, but also the homeostasis of Cl- and bicarbonate (Walz 1995), Na+ (Ballanyi 1995), Ca2+ (Finkbeiner 1995), and the pH (Deitmer 1995).

Astrocytic swelling, known as cytotoxic edema (see below, p. 47), occurs almost immediately following the incidence of CNS injury and has been described in experimental allergic encephalitis (Eng et al. 1989). Axonal swelling probably arises from a trauma or disease-induced increase in levels of potassium, glutamate, fatty acids, arachi-donic acid, lactic acid, and free radicals.

3. Astrocyte-neuron lactate shuttle. According to a recent published hypothesis (Hertz 2004), neuronal activity-induced uptake of glucose takes place predominantly in astrocytes, which metabolize glucose anaerobically while lacate produced from anaerobic glycolysis in astrocytes is then released from astrocytes and provides the primary metabolic fuel for neurons (Chih and Roberts 2003, Hertz and Dienel 2005).

4. Control of vascular tone. Zonta et al. (2003) suggest that neuron-to-astrocyte signaling in the cerebral cortex is central to the dynamic control of vascular tone, and that astrocytes play a crucial role in this process. This conclusion is based on the fact that following electrode stimulation of neuronal afferents Ca2+ levels increase in the somata and endfeet of astrocytes linked to arteri-oles. Thus there is a bridge between the response of astrocytes to neural activity and the observed dilation of arterioles (cf. Reilly 2003).

5. Transmitter inactivation mechanism. Henn and Hamberger (1971) demonstrated the uptake of y-aminobutyric acid (GABA), norepinephrine, dopamine, and serotonin by a cell fraction rich in glial cells, suggesting that glia can eliminate, i.e., take up and metabolize, transmitters that overflow from the synaptic cleft. It is now known that protoplasmic astrocytes in the gray matter perform this function for the aforementioned amino acids and for the excitatory amino acid glutamate, inhibitory adenosine and adenosine triphos-

phate, histamine and N-acetylaspartylglutamate (Martin 1995).

6. Plasma protein uptake. Astrocytes immunostain for albumin (Klatzo et al. 1980), a phenomenon which has prompted some authors to propose that astroglial ingestion of plasma protein might aid in the resolution of brain edema (Oehmichen et al. 1979a; Tomimoto et al. 1996; Del Bigio et al. 2000).

7. Reactivity in CNS injuries. Following mechanical violence to the CNS, astrocytes undergo specific proliferative, morphological, and biochemical changes termed astrogliosis or reactive gliosis (see below, pp. 23f).

8. Immunological activity (for review see Dietrich et al. 2003). Astrocytes are stimulated by the cytokines interleukin-1 (IL-1), IFN-y and tumor necrosis factor-a (TNF-a), as well as by multiple other growth factors (Norenberg 1997). Enlarged (reactive) astrocytes harbor an enhanced number of cytoplasmic organelles plus increased levels of GFAP, Ia antigen, IL-1, a-1-anti-chymotrypsin, and acute phase reactive protein (Eddleston and Mucke 1993).

Under pathological conditions (infiltration by activated T-cells, blood-brain barrier disruption), the CNS shows an increased expression of the class I/II MHC, the adhesion molecule ICAM-1, the TNF-a receptor and complement component C3 (see Morgan 1999) plus production of TNF-a and IL-6 (Benveniste 1997). Astrocytes release various neuroactive compounds when stimulated by neurotransmitters, compounds such as taurine in response to ß-adrenergic stimulation or GABA after glutamate receptor stimulation. A survey of the immune factors synthesized and released by astrocytes -and their effects - was published by Norenberg (1997).

9. Regenerative CNS processes. Gliosis clearly has an inhibitory effect on regeneration of the adult mammalian CNS (Fitch et al. 1999). However, there is also evidence that astrocytes play an active role in both embryonic and adult neurogenesis (Reilly 2002; Song et al. 2002; Svendsen 2002; -for details see p. 66).

10. Neuron-like function. Recent evidence suggests that glial cells play more sophisticated, neuronlike roles; they integrate neuronal input, modulate synaptic activity, and process signals related to learning and memory (Kurosinski and Götz 2002).

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