Standard neurobiology textbooks commonly do not contain a chapter on cancer, and the word might not even appear in the index. Its absence cannot be explained simply on the grounds that the subject falls more appropriately within the clinical realm, because you will find chapters devoted to various other nervous system diseases. Could this intellectual blind spot result from the fact that mature neurons, being post-mitotic, do not succumb to the disease? This absence in most texts is curious, considering the severe functional implications. The word is sometimes used metaphorically to connote an unstoppable process of destruction, and indeed some forms of brain cancer present the most dire prognosis of any cancer. But more importantly the neglect of this subject is curious, because on a molecular and cellular level, cancer is the result of biological processes that are at the forefront of modern neurobiological research. These include such current hot-topic areas as intraand inter-cellular signaling networks, regulation of gene transcription, control of cellular differentiation, regulation of cell motility, migration and cell death; the secretion and response to growth factors, and interactions with the vascular and immune systems. Finally, the current enthusiasm and promising research on the use of stem cells for therapeutic treatment of nervous system disease has brought us face-to-face with our ignorance in this area, as we find that many types of stem cells transplanted into the brain form tumors. This issue of Neuron Glia Biology contains a special collection of original research papers on cancer in the peripheral and central nervous system and a review on the subject. These papers are introduced below by Special Feature Editor, Philip Lee.

In footnote 21 of a groundbreaking paper on astrocyte communication published in Science in 1990, there is a prediction. The authors, Cornell-Bell et al., showed calcium waves propagating widely through monocultures of astrocytes in response to glutamate application. But in the footnote, they cautioned that their observations could be considered in some respects an experimental artifact. The authors believed that instead of the promiscuous propagation of calcium waves spreading throughout the entire population of astrocytes in culture, that in the brain, the communication would be far more discrete and more interesting.

Neuroglia, which are the non-neuronal cells of the nervous system, except for meninges and vasculature with its endothelium, blood vessel walls and relatively rare smooth muscle cells, have received much attention in mammalian investigations and occupy a voluminous literature.

“Of what use a newborn babe?” was Oersted's response to a question from the audience as to the value of electromagnetism following his demonstration that a compass needle could be deflected by passing current through a nearby wire. Such is the immediate reaction anytime something new is encountered: What is it, and why do we need it? This perplexity arises from the certain conclusion of a proof derived from the objective facts: we seem to have managed quite well up to now without it. But as functional as a world before cell phones and email seemed, how dysfunctional would the world now appear without them? Time changes, and Science is change. Scientific journals track and pioneer those changes.

In the CNS, fine processes of astrocytes often wrap around dendrites, axons and synapses, which provides an interface where neurons and astrocytes might interact. We have reported previously that selective Ca2+ elevation in astrocytes, by photolysis of caged Ca2+ by o-nitrophenyl-EGTA (NP-EGTA), causes a kainite receptor-dependent increase in the frequency of spontaneous inhibitory post-synaptic potentials (sIPSCs) in neighboring interneurons in hippocampal slices. However, tetrodotoxin (TTX), which blocks action potentials, reduces the frequency of miniature IPSCs (mIPSCs) in interneurons during Ca2+ uncaging by an unknown presynaptic mechanism. In this study we investigate the mechanism underlying the presynaptic inhibition. We show that Ca2+ uncaging in astrocytes is accompanied by a decrease in the amplitude of evoked IPSCs (eIPSCs) in neighboring interneurons. The decreases in eIPSC amplitude and mIPSC frequency are prevented by CPPG, a group II/III metabotropic glutamate receptor (mGluR) antagonist, but not by the AMPA/kainate and NMDA receptor antagonists CNQX/CPP. Application of either the group II mGluR agonist DCG IV or the group III mGluR agonist L-AP4 decreased the amplitude of eIPSCs by a presynaptic mechanism, and both effects are blocked by CPPG. Thus, activation of mGluRs mediates the effects of Ca2+ uncaging on mIPSCs and eIPSCs. Our results indicate that Ca2+-dependent release of glutamate from astrocytes can activate distinct classes of glutamate receptors and differentially modulate inhibitory synaptic transmission in hippocampal interneurons.

To ensure rapid and efficient impulse conduction, myelinated axons establish and maintain specific protein domains. For instance, sodium (Na+) channels accumulate in the node of Ranvier; potassium (K+) channels aggregate in the juxtaparanode and neurexin/caspr/paranodin clusters in the paranode. Our understanding of the mechanisms that control the initial clustering of these proteins is limited and less is known about domain maintenance. Correlative data indicate that myelin formation and/or mature myelin-forming cells mediate formation of all three domains. Here, we test whether myelin is required for maintaining Na+ channel domains in the nodal gap by employing two demyelinating murine models: (1) cuprizone ingestion, which induces complete demyelination through oligodendrocyte toxicity; and (2) ceramide galactosyltransferase deficient mice, which undergo spontaneous adult-onset demyelination without oligodendrocyte death. Our data indicate that the myelin sheath is essential for long-term maintenance of sodium channel domains; however, oligodendrocytes, independent of myelin, provide a partial protective influence on the maintenance of nodal Na+ channel clusters. Thus, we propose that multiple mechanisms regulate the maintenance of nodal protein organization. Finally, we present evidence that following the loss of Na+ channel clusters the chronological progression of expression and reclustering of Na+ channel isoforms during the course of CNS remyelination recapitulates development.

Activity-dependent neuroprotective protein (ADNP, ∼123562.8 Da), is synthesized in astrocytes and expression of ADNP mRNA is regulated by the neuroprotective peptide vasoactive intestinal peptide (VIP). The gene that encodes ADNP is conserved in human, rat and mouse, and contains a homeobox domain profile that includes a nuclear-export signal and a nuclear-localization signal. ADNP is essential for embryonic brain development, and NAP, an eight-amino acid peptide that is derived from ADNP, confers potent neuroprotection. Here, we investigate the subcellular localization of ADNP through cell fractionation, gel electrophoresis, immunoblotting and immunocytochemistry using α-CNAP, an antibody directed to the neuroprotective NAP fragment that constitutes part of an N-terminal epitope of ADNP. Recombinant ADNP was used as a competitive ligand to measure antibody specificity. ADNP-like immunoreactivity was found in the nuclear cell fraction of astrocytes and in the cytoplasm. In the cytoplasm, ADNP-like immunoreactivity colocalized with tubulin-like immunoreactivity and with microtubular structures, but not with actin microfilaments. Because microtubules are key components of developing neurons and brain, possible interaction between tubulin and ADNP might indicate a functional correlate to the role of ADNP in the brain. In addition, ADNP-like immunoreactivity in the extracellular milieu of astrocytes increased by ∼1.4 fold after incubation of the astrocytes with VIP. VIP is known to cause astrocytes to secrete neuroprotective/neurotrophic factors, and we suggest that ADNP constitutes part of this VIP-stimulated protective milieu.

Glia are required for axon pathfinding along longitudinal trajectories, but it is unknown how this relates to the molecular paradigm of axon guidance across the midline. Most interneuron axons in bilateral organisms cross the midline only once. Preventing them from recrossing the midline requires the expression of Robo receptors on the axons. These sense the repulsive signal Slit, which is produced by the midline. The lateral positioning of longitudinal axons depends on the response to Slit by the combination of Robo receptors expressed by the axons, on selective fasciculation, and on longitudinal (lateral) glia. Here, we analyse how longitudinal glia influence reading of the ‘Robo code’ by axons. We show that whereas loss of robo1 alone only affects the most medial axons, loss of both glial cells missing (gcm) and robo1 causes a severe midline collapse of longitudinal axons, similar to that caused by the loss of multiple Robo receptors. Furthermore, whereas ectopic expression of robo2 is sufficient to displace the medial MP2 axons along a more lateral trajectory, this does not occur in gcm–robo1 double-mutant embryos, where axons either do not extend at all or they misroute exiting the CNS. Hence, lateral neuron–glia interactions steer the response of axons to the Robo code.

Little is known about the functional connectivity between astrocytes in the CNS. To explore this issue we photo-released glutamate onto a single astrocyte in murine hippocampal slices and imaged calcium responses. Photo-release of glutamate causes a metabotropic glutamate receptor (mGluR)-dependent increase in internal calcium in the stimulated astrocyte and delayed calcium elevations in neighboring cells. The delayed elevation in calcium was not caused by either neuronal activity following synaptic transmission or by glutamate released from astrocytes. However, it was reduced by flufenamic acid (FFA), which is consistent with a role for adenosine triphosphate (ATP) release from astrocytes as an intercellular messenger. Exogenous ligands such as ATP (1 µM) increased the number of astrocytes that were recruited into coupled astrocytic networks, indicating that extracellular accumulation of neurotransmitters modulates neuronal excitability, synaptic transmission and functional coupling between astrocytes.

The level of glutathione (GSH) is often reduced in brains that are affected by neurodegeneration. It is not known, however, whether this is a cause or a consequence of the disease. Here we have examined the effects of GSH depletion on the viability of human neurons cultured in either the presence or the absence of astrocytes, both derived from NT2/D1 cells. We established that the endogenous concentration of GSH is 10 times lower in neurons than in astrocytes (1.42 versus 18.9 pmol µg protein−1) and that pure neuronal cultures begin to die by apoptosis within 24 h of GSH depletion. By contrast, neurons that are co-cultured with astrocytes remain viable for several days, even with a profoundly decreased GSH content. However, they die rapidly when challenged additionally with nitrative stress. In addition, astrocytes survive for prolonged periods of time (>12 days) under severely reduced GSH concentrations. Our study shows clear differences in the content and sensitivity to depletion of GSH in neurons and astrocytes and establishes the significance of neuronal–glial interactions for the maintenance of neuronal viability under reduced GSH content. However, with chronic GSH depletion, these interactions might not be sufficient to protect neurons from other injurious factors (i.e. reactive oxygen and nitrogen species), which indicates that defective GSH metabolism might facilitate the progression of neurodegeneration.

Multiple classes of precursor cells have been isolated and characterized from the developing spinal cord including multipotent neuroepithelial (NEP) stem cells and lineage-restricted precursors for neurons (NRPs) and glia (GRPs). We have compared the survival, differentiation and integration of multipotent NEP cells with lineage-restricted NRPs and GRPs using cells isolated from transgenic rats that express the human placental alkaline phosphatase gene. Our results demonstrate that grafted NEP cells survive poorly, with no cells observed 3 days after transplant in the adult hippocampus, striatum and spinal cord, indicating that most CNS regions are not compatible with transplants of multipotent cells derived from fetal CNS. By contrast, at 3 weeks and 5 weeks post-engraftment, lineage-restricted precursors showed selective migration along white-matter tracts and robust survival in all three CNS regions. The grafted precursors expressed the mature neuronal markers NeuN and MAP2, the astrocytic marker GFAP, the oligodendrocytic markers RIP, NG2 and Sox-10, and the synaptic marker synaptophysin. Similar behavior was observed when these precursors were transplanted into the injured spinal cord. Predifferentiated, multipotent NEP cells also survive and integrate, which indicates that lineage-restricted CNS precursors are well suited for transplantation into the adult CNS and provide a promising cellular replacement candidate.

In this review, we discuss examples that show how glial-cell pathology is increasingly recognized in several neurodegenerative diseases. We also discuss the more provocative idea that some of the disorders that are currently considered to be neurodegenerative diseases might, in fact, be due to primary abnormalities in glia. Although the mechanism of glial pathology (i.e. modulating glutamate excitotoxicity) might be better established for amyotrophic lateral sclerosis (ALS), a role for neuronal–glial interactions in the pathogenesis of most neurodegenerative diseases is plausible. This burgeoning area of neuroscience will receive much attention in the future and it is expected that further understanding of basic neuronal–glial interactions will have a significant impact on the understanding of the fundamental nature of human neurodegenerative disorders.

During the past several years, there has been increasing interest in the effects of estrogen on neural function. This enthusiasm is driven, in part, by the results of early clinical studies suggesting that estrogen therapy given after menopause may prevent, or at least delay, the onset of Alzheimer's disease in older women. However, later clinical trials of women with probable Alzheimer's disease had contrary results. Much of the current research related to estrogen and brain function is focused in two directions. One involves clinical studies that examine the potential of estrogen in protecting against cognitive decline during normal aging and against Alzheimer's disease (neuroprotection). The other direction, which is the primary focus of this review, involves laboratory studies that examine the mechanisms by which estrogen can modify the structure of nerve cells and alter the way neurons communicate with other cells in the brain (neuroplasticity). In this review, we examine recent evidence from experimental and clinical research on the rapid effects of estrogen on several mechanisms that involve synaptic plasticity in the nervous system, including hippocampal excitability, long-term potentiation and depression related to sex and aging differences, cellular neuroprotection and probable molecular mechanisms of the action of estrogen in brain tissue.

Transplantation of olfactory ensheathing cells (OECs) into the injured spinal cord has been shown to exert neuroprotective effects and promote functional recovery. In the present study, we investigated the potential modulatory effects of OECs on the inflammatory reaction developed after photochemical injury to the spinal cord. OEC cultures were obtained from olfactory bulbs of adult Sprague-Dawley rats. Photochemical spinal cord injury was induced in adult rats at T8. Thirty minutes after the insult, either a suspension of OECs (180 000 cells in 12 µl DMEM) or DMEM alone was injected into the lesioned spinal cord. At 3, 7 and 14 days post-operation (dpo), five animals from each group were processed for histology. Double-fluorescent labeling of transverse sections of the cord were made by combination of immunohistochemistry for inflammatory markers, interleukin 1β (IL-1β) and inducible nitric oxide synthase (iNOS), and for selective markers of astrocytes (glial fibrillar acidic protein; GFAP) and microglia/macrophages (tomato lectin; LEC). Differences in the intensity and time course of glial response, and IL-1β and iNOS expression were found between the two groups of rats. The reactivity grade against IL-1β, iNOS, GFAP and LEC in OEC-transplanted rats was higher at 7 dpo and lower at 14 dpo compared with DMEM-injected rats. These results indicate that the mechanisms underlying neuroprotection by OECs might be caused by earlier, higher and shorter duration of microglia/macrophage and astrocyte responses after injury.

Based on studies of the molecular and cellular cascades that occur during memory consolidation for a one-trial passive-avoidance learning task in the young chick, I review the evidence that memory is encoded in permanent changes in synaptic connectivity in a specific brain region, the Hebb hypothesis. I conclude that despite the fact that such a cascade occurs, culminating in the synthesis of cell-adhesion molecules that are involved in synaptic remodelling, synaptic events are not in themselves sufficient to account for the phenomena of memory. Both whole brain (neuromodulator) and whole body (hormonal) processes are engaged. Memories are labile, disarticulated and stored in a distributed manner; how the mind/brain recreates coherent memories from this pattern is a mystery.

Synapse formation in the CNS is a complex process that involves the dynamic interplay of numerous signals exchanged between pre- and postsynaptic neurons as well as perisynaptic glia. Members of the neurotrophin family, which are widely expressed in the developing and mature CNS and are well-known for their roles in promoting neuronal survival and differentiation, have emerged as key synaptic modulators. However, the mechanisms by which neurotrophins modulate synapse formation and function are poorly understood. Here, we summarize our work on the role of neurotrophins in synaptogenesis in the CNS, in particular the role of these signaling molecules and their receptors, the Trks, in the development of excitatory and inhibitory hippocampal synapses. We discuss our results that demonstrate that postsynaptic TrkB signaling plays an important role in modulating the formation and maintenance of NMDA and GABAA receptor clusters at central synapses, and suggest that neurotrophin signaling coordinately modulates these receptors as part of mechanism that promotes the balance between excitation and inhibition in developing circuits. We also discuss our results that demonstrate that astrocytes promote the formation of GABAergic synapses in vitro by differentially regulating the development of inhibitory presynaptic terminals and postsynaptic GABAA receptor clusters, and suggest that glial modulation of inhibitory synaptogenesis is mediated by neurotrophin-dependent and -independent signaling. Together, these findings extend our understanding of how neuron–glia communication modulates synapse formation, maintenance and function, and set the stage for defining the cellular and molecular mechanisms by which neurotrophins and other cell–cell signals direct synaptogenesis in the developing brain.

Nonsynaptic release of ATP from electrically stimulated dorsal root gangion (DRG) axons inhibits Schwann cell (SC) proliferation and arrests SC development at the premyelinating stage, but the specific types of purinergic receptor(s) and intracellular signaling pathways involved in this form of neuron–glia communication are not known. Recent research shows that adenosine is a neuron–glial transmitter between axons and myelinating glia of the CNS. The present study investigates the possibility that adenosine might have a similar function in communicating between axons and premyelinating SCs. Using a combination of pharmacological and molecular approaches, we found that mouse SCs in culture express functional adenosine receptors and ATP receptors, a far more complex array of purinergic receptors than thought previously. Adenosine, but not ATP, activates ERK/MAPK through stimulation of cAMP-linked A2A adenosine receptors. Both ATP and adenosine inhibit proliferation of SCs induced by platelet-derived growth factor (PDGF), via mechanisms that are partly independent. In contrast to ATP, adenosine failed to inhibit the differentiation of SCs to the O4+ stage. This indicates that, in addition to ATP, adenosine is an activity-dependent signaling molecule between axons and premyelinating Schwann cells, but that electrical activity, acting through adenosine, has opposite effects on the differentiation of myelinating glia in the PNS and CNS.

Recent evidence argues that the oncogenesis and growth of CNS tumors occurs through dysregulated molecular and cellular mechanisms of neural development. New insights have emerged that have had a significant impact on both research and treatment of these cancers.