All nervous system cell types can be induced with cytokines or bacterial products to make nitric oxide, at least in culture. The signaling pathways invoked by inducers that result in transcriptional activation of the nitric oxide synthase gene are becoming clear, and modulators of this induction have been discovered. Much suggestive and, recently, more definitive evidence has accumulated for induction of nitric oxide synthase in glial cells in vivo associated with viral infection, as well as in animal models of trauma, ischemia, and autoimmunity. Whether nitric oxide from this source contributes to or limits the attendant conditions is not yet clear. The Neuroscientist 2: [90][91][92][93][94][95][96][97][98][99] 1996 It is overly simplistic but convenient to divide the parenchymal, non-neuronal CNS cells into astrocytes, oligodendrocytes, and microglia. Each glial cell type contributes more or less extensively to the development of the CNS and to its steady state functions (for the &dquo;compleat&dquo; account, see reference 1 ). In particular neuropathologies, microglia and astrocytes are activated and contribute to oligodendrocyte and neuron damage and recovery (2-4). One novel but increasingly common currency for intercellular signaling in the CNS is nitric oxide (-NO) (5), a relatively benign and not very reactive gas with a biological half-life of seconds to minutes (6). However, -NO becomes highly reactive through secondary reactions (for example, with O2--) that produce more toxic species (ONOO-and -OH).Three isoforms of NO synthase (NOS) sharing considerable sequence homology catalyze the formation of NO in the nervous system (7). These are designated Types I (NOS 1 ), II (NOS2), and III (NOS3) (the order in which the cDNAs were cloned, not historically according to when their existence was first mooted). NOS3 (&dquo;endothelial&dquo; NOS) is a constitutive and largely membrane-bound enzyme dependent on calcium and calmodulin for activity. NOS is activated by intracellular calcium transients and found constitutively in particular neurons. The suggestion of a constitutive NOS in glial cells arose from observations of the production of a nitrosyl factor from stimulated astrocytes (8). With a variety of antibodies raised against NOS I and also NADPH diaphorase (NADPH-d) histochemistry (an indication of NOS activity under stringent conditions), the presence of NOS I in astrocytes has been verified (9-12).Questions about the nature of this constitutive astrocyte NOS and its role in vivo remain to be answered. In particular, and related to the growing interest in NOS 1 expression during the development of the nervous system (13), such roles for glial-derived NO may include programmed cell death, as well as neuronal guidance and differentiation.NOS2, a dimeric, heme-containing, soluble protein, is independent of calcium for activity (14). First described in activated macrophages, it has now been reported in a wide variety of normal and neoplastic cell types. In the CNS, all parenchymal and cerebrovascular cel...