The multifaceted role of glial cells in amyotrophic lateral sclerosis

Despite indisputable progress in the molecular and genetic aspects of amyotrophic lateral sclerosis (ALS), a mechanistic comprehension of the neurodegenerative processes typical of this disorder is still missing and no effective cures to halt the progression of this pathology have yet been developed. Therefore, it seems that a substantial improvement of the outcome of ALS treatments may depend on a better understanding of the molecular mechanisms underlying neuronal pathology and survival as well as on the establishment of novel etiological therapeutic strategies. Noteworthy, a convergence of recent data from multiple studies suggests that, in cellular and animal models of ALS, a complex pathological interplay subsists between motor neurons and their non-neuronal neighbours, particularly glial cells. These observations not only have drawn attention to the physiopathological changes glial cells undergo during ALS progression, but they have moved the focus of the investigations from intrinsic defects and weakening of motor neurons to glia–neuron interactions. In this review, we summarize the growing body of evidence supporting the concept that different glial populations are critically involved in the dreadful chain of events leading to motor neuron sufferance and death in various forms of ALS. The outlined observations strongly suggest that glial cells can be the targets for novel therapeutic interventions in ALS.     

Comparing peripheral glial cell differentiation in <Emphasis Type="Italic">Drosophila</Emphasis> and vertebrates

In all complex organisms, the peripheral nerves ensure the portage of information from the periphery to central computing and back again. Axons are in part amazingly long and are accompanied by several different glial cell types. These peripheral glial cells ensure electrical conductance, most likely nuture the long axon, and establish and maintain a barrier towards extracellular body fluids. Recent work has revealed a surprisingly similar organization of peripheral nerves of vertebrates and Drosophila. Thus, the genetic dissection of glial differentiation in Drosophila may also advance our understanding of basic principles underlying the development of peripheral nerves in vertebrates.     

Immunohistochemical localization of S-100 protein in human cerebral and cerebellar cortices

Summary S-100 protein, a highly acidic protein specific to the nervous system, is immunohistochemically localized exclusively in glial cells, but not in any type of neuron in human cerebral and cerebellar cortices.     

Pigment-dispersing hormone in <Emphasis Type="Italic">Daphnia</Emphasis> interneurons,one type homologous to insect clock neurons displaying circadian rhythmicity

We report identification of a beta-type pigment-dispersing hormone (PDH) identical in two water flea species, Daphnia magna and Daphnia pulex. It has been identified by cloning of precursors, chromatographic isolation from tissue extracts followed by immunoassays and de novo-mass spectrometric sequencing. The peptide is restricted to a complex system of distinct interneurons in the brain and visual ganglia, but does not occur in neurosecretory cells projecting to neurohemal organs as in decapod crustaceans. Thirteen neuron types individually identified and reconstructed by immunohistochemistry were almost identical in terms of positions and projection patterns in both species. Several neurons invade and form plexuses in visual ganglia and major brain neuropils including the central body. Five neuron types show contralateral pathways and form plexuses in the lateral, dorsal, or postlateral brain neuropils. Others are local interneurons, and a tritocerebral neuron connects the protocerebrum with the neuropil of the locomotory second antenna. Two visual ganglia neuron types lateral to the medulla closely resemble insect medulla lateral circadian clock neurons containing pigment-dispersing factor based upon positional and projectional criteria. Experiments under 12:12 h light/dark cycles and constant light or darkness conditions showed significant circadian changes in numbers and activities of one type of medulla lateral PDH neuron with an acrophase in the evening. This simple PDH system shows striking homologies to PDH systems in decapod crustaceans and well-known clock neurons in several insects, which suggests evolutionary conservation of an ancient peptidergic interneuronal system that is part of biological clocks.     

A newTrichoplusia ni antennal receptor neuron that responds to attomolar concentrations of a minor pheromone component

Summary A newly discovered third class of sensillum trichodea on the antenna ofTrichoplusia ni contains an olfactory receptor neuron that responds to (Z)-9-tetradecen-1-ol acetate at 1×10^–18 M. The threshold of this neuron is 100–1000 times lower than the thresholds of two previously described pheromone-sensitive neurons that detect (Z)-7-dodecen-1-ol acetate and (Z)-7-tetradecen-1-ol acetate. The sensitivity and selectivity of this receptor neuron is evidence that (Z)-9-tetradecen-1-ol acetate may be important for sexual behavior.     

The role of bHLH genes in ear development and evolution: revisiting a 10-year-old hypothesis

In mouse ear development, two bHLH genes, Atoh1 and Neurog1, are essential for hair cell and sensory neuron differentiation. Evolution converted the original simple atonal-dependent neurosensory cell formation program of diploblasts into the derived developmental program of vertebrates that generates two neurosensory cell types, the sensory neuron and the sensory hair cell. This transformation was achieved through gene multiplication in ancestral triploblasts resulting in the expansion of the atonal bHLH gene family. Novel genes of the Neurogenin and NeuroD families are upregulated prior to the expression of Atoh1. Recent data suggest that NeuroD and Neurogenin were lost or their function in neuronal specification reduced in flies, thus changing our perception of the evolution of these genes. This sequence of expression changes was accompanied by modification of the E-box binding sites of these genes to regulate different downstream genes and to form inhibitory loops among each other, thus fine-tuning expression transitions.     

Methionine enkephalin inhibits the bursting activity of the Br-type neuron inHelix pomatia L.

Summary The present study demonstrates that methionine enkephalin can inhibit the normal bursting activity pattern of the RPal or Br-type neuron and this inhibition can be blocked by prior treatment with naloxone, the selective opiate antagonist. The study demonstrates indirectly the presence of opiate-like receptors inHelix pomatia.Acknowledgments. This work was funded by grant RR 08171 Division of Research Resources and NIMH, and a National Academy of Sciences Travel grant and a Hungarian Academy of Sciences research support award to G.B.S. We also gratefully acknowledge thoughtful comments from Dr J. Salanki.     

Effect of olfactory ensheathing cells on reactive astrocytes <Emphasis Type="Italic">in vitro</Emphasis>

Olfactory ensheathing cells have been used in several studies to promote repair in the injured spinal cord. However, cellular interaction between olfactory ensheathing cells and glial cells induced to be reactive in the aftermath of injury site has not been investigated. Using an in vitro model of astrogliosis, we show that reactive astrocytes expressed significantly less glial fibrillary acidic protein (GFAP) when cultured both in direct contact with olfactory ensheathing cells and when the two cell types were separated by a porous membrane. Immunofluorescence staining also suggested that reactive astrocytes showed decreased chondroitin sulfate proteoglycans in the presence of olfactory ensheathing cells, although the reduction was not statistically significant. No down-regulation of GFAP was observed when reactive astrocytes were similarly cultured with Schwann cells. Cell viability assay and bromodeoxyuridine uptake showed that proliferation of reactive astrocytes was significantly increased in the presence of olfactory ensheathing cells and Schwann cells. Received 27 February 2007; received after revision 30 March 2007; accepted 3 April 2007     

Optical monitoring of activity of many neurons in invertebrate ganglia during behaviors

Summary Optical methods for monitoring neuron activity were developed because these methods lend themselves to simultaneous multiple-site measurements. With the use of new voltage-sensitive dyes, the dye-related pharmacology and photodynamic damage appear to be relatively unimportant. Using multiple-site measurements made with a 124-element photodiode array, we estimated that approximately 30 of the 200 neurons present in theNavanax buccal ganglion make action potentials during feeding and that approximately 300 of the 1100 neurons present in theNavanax buccal ganglion make are active during the gill-withdrawal reflex. The fact that a light mechanical touch to the siphon skin activated such a large number of neurons in the abdominal ganglion suggests that understanding the neuronal basis of the gill-withdrawal reflex and its behavioral plasticity may be forbiddingly difficult.     

Uptake ofl-glutamate andl-aspartate in neurones and glial cells of cultured human and rat spinal cord

Summary Autoradiographic investigations on the uptake ofl-glutamate andl-aspartate have shown that the amino acids were taken up by neurones as well as by glial cells of cultured human and rat spinal cord. The activity of glutamate and aspartate varied considerably between individual neurones, whereas glial cells showed a more even distribution of the labelled amino acids. Our results suggest that both neurones and glial cells are involved in the uptake of amino acid transmitters.     

Molecular neurophysiology of taste in <Emphasis Type="Italic">Drosophila</Emphasis>

The recent identification of candidate receptor genes for sweet, umami and bitter taste in mammals has opened a door to elucidate the molecular and neuronal mechanisms of taste. Drosophila provides a suitable system to study the molecular, physiological and behavioral aspects of taste, as sophisticated molecular genetic techniques can be applied. A gene family for putative gustatory receptors has been found in the Drosophila genome. We discuss here current knowledge of the gustatory physiology of Drosophila. Taste cells in insects are primary sensory neurons whereupon each receptor neuron responds to either sugar, salt or water. We found that particular tarsal gustatory sensilla respond to bitter compounds. Electrophysiological studies indicate that gustatory sensilla on the labellum and tarsi are heterogeneous in terms of their taste sensitivity. Determination of the molecular bases for this heterogeneity could lead to an understanding of how the sensory information is processed in the brain and how this in turn is linked to behavior.Received 12 May 2003; received after revision 9 June 2003; accepted 13 June 2003     

Bestimmung des DNS-Gehaltes in Zellkernen des Nervengewebes vonHelix pomatia L. undPlanorbarius corneus L. (Stylommatophora und Basommatophora,Gastropoda)

Summary It has been demonstrated by cytophotometric measurements of the DNA-content in glial- and nerve cells of the snailsHelix pomatia (Stylommatophora) andPlanorbarius corneus (Basommatophora) that the giant nuclei of nerve cells in the central ganglia contain more than tens of thousands of DNA compared with sperm nuclei. According to the DNA-content of sperms (=n), the values for glial cells are between 2n and 4n for both species.

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Herrn Prof. Dr. W.Dittrich, Institut für Strahlenbiologie der Universität Münster, danke ich für die Möglichkeit, am UMSP I arbeiten zu dürfen; Frl. A.Stipproweit danke ich für sorgfältige technische Assistenz.     

Wnt and lithium: a common destiny in the therapy of nervous system pathologies?

Wnt signaling is required for neurogenesis, the fate of neural progenitors, the formation of neuronal circuits during development, neuron positioning and polarization, axon and dendrite development and finally for synaptogenesis. This signaling pathway is also implicated in the generation and differentiation of glial cells. In this review, we describe the mechanisms of action of Wnt signaling pathways and their implication in the development and correct functioning of the nervous system. We also illustrate how a dysregulated Wnt pathway could lead to psychiatric, neurodegenerative and demyelinating pathologies. Lithium, used for the treatment of bipolar disease, inhibits GSK3β, a central enzyme of the Wnt/β-catenin pathway. Thus, lithium could, to some extent, mimic Wnt pathway. We highlight the possible dialogue between lithium therapy and modulation of Wnt pathway in the treatment of the diseases of the nervous system.     

The Light Green Cells ofLymnaea: A neuroendocrine model system for stimulus-induced expression of multiple peptide genes in a single cell type

We review recent experiments showing that the cerebral neuroendocrine Light Green Cells (LGCs) of the freshwater snail,Lymnaea stagnalis, express a family of distinct though related molluscan insulin-related peptide (MIP) genes. The LGCs are involved in the regulation of a wide range of interrelated life processes associated with growth, (energy) metabolism and reproduction. We consider the mechanism of generation of diversity among MIPs, and present evidence that conditions with distinct effects on growth, metabolism and reproduction also can induce distinct patterns of expression of the MIP and schistosomin genes. The stimulus-dependent expression of multiple neuropeptide genes enormously increases the adaptive potential of a peptidergic neuron. We suggest that this contributes significantly to the information-handling capacity of the brain.     

Coaxing bone marrow stromal mesenchymal stem cells towards neuronal differentiation: progress and uncertainties

Multipotent adult stem cells capable of developing into particular neuronal cell types have great potential for autologous cell replacement therapy for central nervous system neurodegenerative disorders and traumatic injury. Bone marrow-derived stromal mesenchymal stem cells (BMSCs) appear to be attractive starting materials. One question is whether BMSCs could be coaxed to differentiate in vitro along neuronal or glial lineages that would aid their functional integration post-transplantation, while reducing the risk of malignant transformation. Recent works suggest that BMSCs could indeed be differentiated in vitro to exhibit some cellular and physiological characteristics of neural cell lineages, but it is not likely to be achievable with simple chemical treatments. We discussed recent findings pertaining to efforts in neuronal differentiation of BMSCs in vitro, and results obtained when these were transplanted in vivo. Received 19 January 2006; received after revision 24 February 2006; accepted 12 April 2006     

Olfactory receptors

Olfaction is an ancient sensory system allowing an organism to detect chemicals in its environment. The first step in odor transduction is mediated by binding odorants to olfactory receptors (ORs) which belong to the heptahelical G-protein-coupled receptor (GPCR) superfamily. Mammalian ORs are disposed in clusters on virtually all chromosomes. They are encoded by the largest multigene family (1000 members) in the genome of mammals and Caenorhabditis elegans, whereas Drosophila contains only 60 genes. Each OR specifically recognizes a set of odorous molecules that share common molecular features. In mammals, signal transduces through the G-protein-dependent signal pathway in the olfactory sensory neurons that synapse ultimately in the glomeruli of the olfactory bulb, and is finally processed in higher brain structures. The expression of a given OR conditions neuron and glomerulus choices. To date, the processes which monitor OR expression and axon wiring have emerged but are not completely elucidated.Received 9 July 2003; reiceived after revision 3 Ocotober 2003; accepted 22 Ocotober 2003     

Stem cell transplantation for amyotrophic lateral sclerosis: therapeutic potential and perspectives on clinical translation

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by degeneration of upper and lower motor neurons. There are currently no clinically impactful treatments for this disorder. Death occurs 3–5 years after diagnosis, usually due to respiratory failure. ALS pathogenesis seems to involve several pathological mechanisms (i.e., oxidative stress, inflammation, and loss of the glial neurotrophic support, glutamate toxicity) with different contributions from environmental and genetic factors. This multifaceted combination highlights the concept that an effective therapeutic approach should counteract simultaneously different aspects: stem cell therapies are able to maintain or rescue motor neuron function and modulate toxicity in the central nervous system (CNS) at the same time, eventually representing the most comprehensive therapeutic approach for ALS. To achieve an effective cell-mediated therapy suitable for clinical applications, several issues must be addressed, including the identification of the most performing cell source, a feasible administration protocol, and the definition of therapeutic mechanisms. The method of cell delivery represents a major issue in developing cell-mediated approaches since the cells, to be effective, need to be spread across the CNS, targeting both lower and upper motor neurons. On the other hand, there is the need to define a strategy that could provide a whole distribution without being too invasive or burdened by side effects. Here, we review the recent advances regarding the therapeutic potential of stem cells for ALS with a focus on the minimally invasive strategies that could facilitate an extensive translation to their clinical application.     

Chemokines in neuron–glial cell interaction and pathogenesis of neuropathic pain

Neuropathic pain resulting from damage or dysfunction of the nervous system is a highly debilitating chronic pain state and is often resistant to currently available treatments. It has become clear that neuroinflammation, mainly mediated by proinflammatory cytokines and chemokines, plays an important role in the establishment and maintenance of neuropathic pain. Chemokines were originally identified as regulators of peripheral immune cell trafficking and were also expressed in neurons and glial cells in the central nervous system. In recent years, accumulating studies have revealed the expression, distribution and function of chemokines in the spinal cord under chronic pain conditions. In this review, we provide evidence showing that several chemokines are upregulated after peripheral nerve injury and contribute to the pathogenesis of neuropathic pain via different forms of neuron–glia interaction in the spinal cord. First, chemokine CX3CL1 is expressed in primary afferents and spinal neurons and induces microglial activation via its microglial receptor CX3CR1 (neuron-to-microglia signaling). Second, CCL2 and CXCL1 are expressed in spinal astrocytes and act on CCR2 and CXCR2 in spinal neurons to increase excitatory synaptic transmission (astrocyte-to-neuron signaling). Third, we recently identified that CXCL13 is highly upregulated in spinal neurons after spinal nerve ligation and induces spinal astrocyte activation via receptor CXCR5 (neuron-to-astrocyte signaling). Strategies that target chemokine-mediated neuron-glia interactions may lead to novel therapies for the treatment of neuropathic pain.     

Alexander disease: putative mechanisms of an astrocytic encephalopathy

Alexander disease (AXD) is the first primary astrocytic disorder. This encephalopathy is caused by dominant mutations in the glial fibrillary acidic protein (GFAP) gene, encoding the main intermediate filament of astrocyte. Pathologically, this neurodegenerative disease is characterised by dystrophic astrocytes containing intermediate filament aggregates associated with myelin abnormalities.More than 20 GFAP mutations have been reported. Many of them cluster in highly conserved regions between several intermediate filaments. Contrary to other intermediate filament-related diseases, AXD seems to be the consequence of a toxic gain of function induced by aggregates. This is supported by the phenotype of mice overexpressing human GFAP. Nevertheless, GFAP null mice display myelin abnormalities and blood-brain barrier dysfunction that are present in AXD.Given the pivotal role of astrocytes in brain physiology, there are many possibilities for astrocytes to dysfunction and to impair the functions of other cells. Physiopathological hypotheses are discussed in the frame of AXD.Received 11 April 2003; received after revision 22 July 2003; accepted 31 July 2003Both authors contributed equally to this work.     

Hes-1 regulates the excitatory fate of neural progenitors through modulation of <Emphasis Type="Italic">Tlx3 (HOX11L2)</Emphasis> expression

Tlx3 (HOX11L2) is regarded as one of the selector genes in excitatory versus inhibitory fate specification of neurons in distinct regions of the nervous system. Expression of Tlx3 in a post-mitotic immature neuron favors a glutamatergic over GABAergic fate. The factors that regulate Tlx3 have immense importance in the fate specification of glutamatergic neurons. Here, we have shown that Notch target gene, Hes-1, negatively regulates Tlx3 expression, resulting in decreased generation of glutamatergic neurons. Down-regulation of Hes-1 removed the inhibition on Tlx3 promoter, thus promoting glutamatergic differentiation. Promoter–protein interaction studies with truncated/mutated Hes-1 protein suggested that the co-repressor recruitment mediated through WRPW domain of Hes-1 has contributed to the repressive effect. Our results clearly demonstrate a new and unique role for canonical Notch signaling through Hes-1, in neurotransmitter/subtype fate specification of neurons in addition to its known functional role in proliferation/maintenance of neural progenitors.