Astrocytes in the aging brain

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. 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). 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). 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). 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. 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