Showing papers on "Nervous system published in 2009"
TL;DR: The major triggers that initiate and maintain central sensitization in healthy individuals in response to nociceptor input and in patients with inflammatory and neuropathic pain are reviewed, emphasizing the fundamental contribution and multiple mechanisms of synaptic plasticity caused by changes in the density, nature, and properties of ionotropic and metabotropic glutamate receptors.
2,803 citations
TL;DR: Treatment needs to move from merely suppressing symptoms to a disease-modifying strategy aimed at both preventing maladaptive plasticity and reducing intrinsic risk.
Abstract: Neuropathic pain is triggered by lesions to the somatosensory nervous system that alter its structure and function so that pain occurs spontaneously and responses to noxious and innocuous stimuli are pathologically amplified. The pain is an expression of maladaptive plasticity within the nociceptive system, a series of changes that constitute a neural disease state. Multiple alterations distributed widely across the nervous system contribute to complex pain phenotypes. These alterations include ectopic generation of action potentials, facilitation and disinhibition of synaptic transmission, loss of synaptic connectivity and formation of new synaptic circuits, and neuroimmune interactions. Although neural lesions are necessary, they are not sufficient to generate neuropathic pain; genetic polymorphisms, gender, and age all influence the risk of developing persistent pain. Treatment needs to move from merely suppressing symptoms to a disease-modifying strategy aimed at both preventing maladaptive plasticity and reducing intrinsic risk.
1,616 citations
TL;DR: A wealth of data now demonstrate that the microglia have very diverse effector functions, in line with macrophage populations in other organs, and the term activatedmicroglia needs to be qualified to reflect the distinct and very different states of activation-associated effector function in different disease states.
Abstract: Microglia, the macrophages of the central nervous system parenchyma, have in the normal healthy brain a distinct phenotype induced by molecules expressed on or secreted by adjacent neurons and astrocytes, and this phenotype is maintained in part by virtue of the blood-brain barrier's exclusion of serum components. Microglia are continually active, their processes palpating and surveying their local microenvironment. The microglia rapidly change their phenotype in response to any disturbance of nervous system homeostasis and are commonly referred to as activated on the basis of the changes in their morphology or expression of cell surface antigens. A wealth of data now demonstrate that the microglia have very diverse effector functions, in line with macrophage populations in other organs. The term activated microglia needs to be qualified to reflect the distinct and very different states of activation-associated effector functions in different disease states. Manipulating the effector functions of microglia has the potential to modify the outcome of diverse neurological diseases.
1,611 citations
TL;DR: Enterochromaffin cells are important bidirectional transducers that regulate communication between the gut lumen and the nervous system, and may have an important role in pain and immune-response modulation, control of background emotions and other homeostatic functions.
Abstract: While bidirectional brain-gut interactions are well known mechanisms for the regulation of gut function in both healthy and diseased states, a role of the enteric flora--including both commensal and pathogenic organisms--in these interactions has only been recognized in the past few years. The brain can influence commensal organisms (enteric microbiota) indirectly, via changes in gastrointestinal motility and secretion, and intestinal permeability, or directly, via signaling molecules released into the gut lumen from cells in the lamina propria (enterochromaffin cells, neurons, immune cells). Communication from enteric microbiota to the host can occur via multiple mechanisms, including epithelial-cell, receptor-mediated signaling and, when intestinal permeability is increased, through direct stimulation of host cells in the lamina propria. Enterochromaffin cells are important bidirectional transducers that regulate communication between the gut lumen and the nervous system. Vagal, afferent innervation of enterochromaffin cells provides a direct pathway for enterochromaffin-cell signaling to neuronal circuits, which may have an important role in pain and immune-response modulation, control of background emotions and other homeostatic functions. Disruption of the bidirectional interactions between the enteric microbiota and the nervous system may be involved in the pathophysiology of acute and chronic gastrointestinal disease states, including functional and inflammatory bowel disorders.
944 citations
TL;DR: The extensive and diverse requirements for properly regulated cytokine signaling during normal nervous system development revealed by these studies sets the foundation for ongoing and future work aimed at understanding how cytokines induced normally and pathologically during critical stages of fetal development alter nervous system function and behavior later in life.
745 citations
TL;DR: The neuronal thrombospondin receptor involved in CNS synapse formation is identified as alpha2delta-1, the receptor for the anti-epileptic and analgesic drug gabapentin and suggested that gapapentin may function therapeutically by blocking new synapses formation.
699 citations
TL;DR: The molecular properties of VEGF and its receptors are described and the current knowledge of its different functions and therapeutic potential in the nervous system during development, health, disease and in medicine is reviewed.
Abstract: The development of the nervous and vascular systems constitutes primary events in the evolution of the animal kingdom; the former provides electrical stimuli and coordination, while the latter supplies oxygen and nutrients. Both systems have more in common than originally anticipated. Perhaps the most striking observation is that angiogenic factors, when deregulated, contribute to various neurological disorders, such as neurodegeneration, and might be useful for the treatment of some of these pathologies. The prototypic example of this cross-talk between nerves and vessels is the vascular endothelial growth factor or VEGF. Although originally described as a key angiogenic factor, it is now well established that VEGF also plays a crucial role in the nervous system. We describe the molecular properties of VEGF and its receptors and review the current knowledge of its different functions and therapeutic potential in the nervous system during development, health, disease and in medicine.
404 citations
TL;DR: Inhibition of NF-kappaB in glia might ameliorate disease, whereas activation in neurons might enhance memory, and this review focuses on results produced by the analysis of genetic models.
Abstract: The transcription factor NF-kappaB has diverse functions in the nervous system, depending on the cellular context. NF-kappaB is constitutively activated in glutamatergic neurons. Knockout of p65 or inhibition of neuronal NF-kappaB by super-repressor IkappaB resulted in the loss of neuroprotection and defects in learning and memory. Similarly, p50-/- mice have a lower learning ability and are sensitive to neurotoxins. Activated NF-kappaB can be transported retrogradely from activated synapses to the nucleus to translate short-term processes to long-term changes such as axon growth, which is important for long-term memory. In glia, NF-kappaB is inducible and regulates inflammatory processes that exacerbate diseases such as autoimmune encephalomyelitis, ischemia, and Alzheimer's disease. In summary, inhibition of NF-kappaB in glia might ameliorate disease, whereas activation in neurons might enhance memory. This review focuses on results produced by the analysis of genetic models.
339 citations
TL;DR: Determinants of axon regeneration in the PNS and CNS are discussed, where both extracellular molecules and the intrinsic growth capacity of the neuron influence regenerative success.
Abstract: Axon regeneration in the mature mammalian central nervous system (CNS) is extremely limited after injury. Consequently, functional deficits persist after spinal cord injury (SCI), traumatic brain injury, stroke, and related conditions that involve axonal disconnection. This situation differs from that in the mammalian peripheral nervous system (PNS), where long-distance axon regeneration and substantial functional recovery can occur in the adult. Both extracellular molecules and the intrinsic growth capacity of the neuron influence regenerative success. This chapter discusses determinants of axon regeneration in the PNS and CNS.
322 citations
TL;DR: It is shown that SPR expression in these fru+ ppk+ neurons is both necessary and sufficient for behavioral changes induced by mating, and project to regions of the central nervous system that have been implicated in the control of reproductive behaviors in Drosophila and other insects.
253 citations
TL;DR: It is concluded that raphé 5-HT neurons excite key circuit components required for generation of respiratory motor output in neonatal and juvenile rats, and can transform the electrophysiological phenotype of some pre-BötC neurons to intrinsic bursters, providing 5- HT with an additional role in promoting rhythm generation.
Abstract: Brainstem serotonin (5-HT) neurons modulate activity of many neural circuits in the mammalian brain, but in many cases endogenous mechanisms have not been resolved. Here, we analyzed actions of raphe 5-HT neurons on respiratory network activity including at the level of the pre-Botzinger complex (pre-BotC) in neonatal rat medullary slices in vitro, and in the more intact nervous system of juvenile rats in arterially perfused brainstem–spinal cord preparations in situ. At basal levels of activity, excitation of the respiratory network via simultaneous release of 5-HT and substance P (SP), acting at 5-HT2A/2C, 5-HT4, and/or neurokinin-1 receptors, was required to maintain inspiratory motor output in both the neonatal and juvenile systems. The midline raphe obscurus contained spontaneously active 5-HT neurons, some of which projected to the pre-BotC and hypoglossal motoneurons, colocalized 5-HT and SP, and received reciprocal excitatory connections from the pre-BotC. Experimentally augmenting raphe obscurus activity increased motor output by simultaneously exciting pre-BotC and motor neurons. Biophysical analyses in vitro demonstrated that 5-HT and SP modulated background cation conductances in pre-BotC and motor neurons, including a nonselective cation leak current that contributed to the resting potential, which explains the neuronal depolarization that augmented motor output. Furthermore, we found that 5-HT, but not SP, can transform the electrophysiological phenotype of some pre-BotC neurons to intrinsic bursters, providing 5-HT with an additional role in promoting rhythm generation. We conclude that raphe 5-HT neurons excite key circuit components required for generation of respiratory motor output.
TL;DR: It is demonstrated that nerve cells that overexpress tagged α-synuclein can transmit the protein to neural stem cells in both in vitro and in vivo models, which could explain the remarkable finding that human embryonic dopamine nerve cells implanted into the striatum of patients with Parkinson's disease develop PD pathology with loss of dopamine markers and classic Lewy bodies.
Abstract: In this issue of PNAS, Desplats et al. (1) demonstrate that nerve cells that overexpress tagged α-synuclein can transmit the protein to neural stem cells in both in vitro and in vivo models. This important study could explain the remarkable finding that human embryonic dopamine nerve cells implanted into the striatum of patients with Parkinson's disease (PD) develop PD pathology with loss of dopamine markers and classic Lewy bodies (2, 3). It also provides insight into how α-synuclein pathology might sequentially spread throughout the nervous system in PD.
TL;DR: It is demonstrated that one can excite specific neurons expressing ChR2 while simultaneously monitoring G-CaMP fluorescence in several other neurons, making it possible to rapidly decipher functional connections in C. elegans neural circuits.
Abstract: The nematode Caenorhabditis elegans has a compact nervous system with only 302 neurons. Whereas most of the synaptic connections between these neurons have been identified by electron microscopy serial reconstructions, functional connections have been inferred between only a few neurons through combinations of electrophysiology, cell ablation, in vivo calcium imaging and genetic analysis. To map functional connections between neurons, we combined in vivo optical stimulation with simultaneous calcium imaging. We analyzed the connections from the ASH sensory neurons and RIM interneurons to the command interneurons AVA and AVD. Stimulation of ASH or RIM neurons using channelrhodopsin-2 (ChR2) resulted in activation of AVA neurons, evoking an avoidance behavior. Our results demonstrate that we can excite specific neurons expressing ChR2 while simultaneously monitoring G-CaMP fluorescence in several other neurons, making it possible to rapidly decipher functional connections in C. elegans neural circuits.
TL;DR: It is shown that presynaptic terminals regulate astroglial synaptic functions, GLT1/EAAT2, via kappa B-motif binding phosphoprotein (KBBP), the mouse homolog of human heterogeneous nuclear ribonucleoprotein K (hnRNP K), which binds the GLT 1/EAat2 promoter.
TL;DR: Early neurons and stem cell populations identified with NvMsi, NvELAV, and NvGCM, indicate that neural differentiation occurs throughout the animal and initiates prior to the conclusion of gastrulation.
Abstract: Nematostella vectensis, an anthozoan cnidarian, whose genome has been sequenced and is suitable for developmental and ecological studies, has a complex neural morphology that is modified during development from the larval to adult form. N. vectensis' nervous system is a diffuse nerve net with both ectodermal sensory and effector cells and endodermal multipolar ganglion cells. This nerve net consists of several distinct neural territories along the oral-aboral axis including the pharyngeal and oral nerve rings, and the larval apical tuft. These neuralized regions correspond to expression of conserved bilaterian neural developmental regulatory genes including homeodomain transcription factors and NCAMs. Early neurons and stem cell populations identified with NvMsi, NvELAV, and NvGCM, indicate that neural differentiation occurs throughout the animal and initiates prior to the conclusion of gastrulation. Neural specification in N. vectensis appears to occur through an independent mechanism from that in the classical cnidarian model Hydra.
TL;DR: The reinnervation of brainstem targets after SCI is reported for the first time and an essential role for chemotropic axon guidance in target selection is reported.
Abstract: A principal objective of spinal cord injury (SCI) research is the restoration of axonal connectivity to denervated targets. We tested the hypothesis that chemotropic mechanisms would guide regenerating spinal cord axons to appropriate brainstem targets. We subjected rats to cervical level 1 (C1) lesions and combinatorial treatments to elicit axonal bridging into and beyond lesion sites. Lentiviral vectors expressing neurotrophin-3 (NT-3) were then injected into an appropriate brainstem target, the nucleus gracilis, and an inappropriate target, the reticular formation. NT-3 expression in the correct target led to reinnervation of the nucleus gracilis in a dose-related fashion, whereas NT-3 expression in the reticular formation led to mistargeting of regenerating axons. Axons regenerating into the nucleus gracilis formed axodendritic synapses containing rounded vesicles, reflective of pre-injury synaptic architecture. Thus, we report for the first time, to the best of our knowledge, the reinnervation of brainstem targets after SCI and an essential role for chemotropic axon guidance in target selection.
TL;DR: It is shown that nSR100 regulates an extensive network of brain-specific alternative exons enriched in genes that function in neural cell differentiation and acts by increasing the levels of the neural/brain-enriched polypyrimidine tract binding protein and by interacting with its target transcripts.
TL;DR: The semaphorins, originally discovered as evolutionarily conserved steering molecules for developing axons, also influence neuronal structure and function in the early postnatal and juvenile nervous systems through several refinement processes.
TL;DR: There are six pairs of nerves, of which the sixth and most posterior are referred to as recurrent nerves since they join the first nerve of the ganglion in the metathorax.
Abstract: A description is given of those nerves which arise from the mesothoracic ganglion of Locusta migratoria migratorioides R. & F. There are six pairs of nerves, of which the sixth and most posterior are referred to as recurrent nerves since they join the first nerve of the ganglion in the metathorax. The median nerve is also described. The posterior median nerve of the prothoracic ganglion is noted as its branches make a connection with the branches of the first mesothoracic nerve. Wherever possible an attempt has been made to relate the observations to those of some other authors.
TL;DR: It is found that single-walled CNTs with different degrees of agglomeration reduce the amount of glial cells in both peripheral nervous system and central nervous system derived cultures, and if SWCNTs can enter the nervous system at sufficiently high concentrations, it is likely that adverse effects onglial cells and neurons might occur.
Abstract: Carbon nanotubes (CNTs) are among the most promising novel nanomaterials and their unique chemical and physical properties suggest an enormous potential for many areas of research and applications. As a consequence, the production of CNT-based material and thus the occupational and public exposure to CNTs will increase steadily. Although there is evidence that nanoparticles (NPs) can enter the nervous system via the blood stream, olfactory nerves or sensory nerves in the skin, there is still only little knowledge about possible toxic effects of CNTs on cells of the nervous system. The goal of the present study was to analyse the influences of single-walled CNTs (SWCNTs) with different degrees of agglomeration on primary cultures derived from chicken embryonic spinal cord (SPC) or dorsal root ganglia (DRG). As measured by the Hoechst assay treatment of mixed neuro-glial cultures with up to 30mug/mL SWCNTs significantly decreased the overall DNA content. This effect was more pronounced if cells were exposed to highly agglomerated SWCNTs as compared to better dispersed SWCNT-bundles. Using a cell-based ELISA we found that SWCNTs reduce the amount of glial cells in both peripheral nervous system (PNS) and central nervous system (CNS) derived cultures. Neurons were only affected in DRG derived cultures, where SWCNT treatment resulted in a decreased number of sensory neurons, as measured by ELISA. Additionally, whole-cell patch recordings revealed a diminished inward conductivity and a more positive resting membrane potential of SWCNT treated DRG derived neurons compared to control samples. The SWCNT suspensions used in this study induced acute toxic effects in primary cultures from both, the central and peripheral nervous system of chicken embryos. The level of toxicity is at least partially dependent on the agglomeration state of the tubes. Thus if SWCNTs can enter the nervous system at sufficiently high concentrations, it is likely that adverse effects on glial cells and neurons might occur.
TL;DR: It is found that rAAV2/6 is an efficient vector to deliver transgenes to nociceptive neurons in mice and the characterization of the transduction profile may facilitate gene transfer studies to dissect mechanisms behind neuropathic pain.
Abstract: Gene transfer to nociceptive neurons of the dorsal root ganglia (DRG) is a promising approach to dissect mechanisms of pain in rodents and is a potential therapeutic strategy for the treatment of persistent pain disorders such as neuropathic pain. A number of studies have demonstrated transduction of DRG neurons using herpes simplex virus, adenovirus and more recently, adeno-associated virus (AAV). Recombinant AAV are currently the gene transfer vehicles of choice for the nervous system and have several advantages over other vectors, including stable and safe gene expression. We have explored the capacity of recombinant AAV serotype 6 (rAAV2/6) to deliver genes to DRG neurons and characterized the transduction of nociceptors through five different routes of administration in mice. Direct injection of rAAV2/6 expressing green fluorescent protein (eGFP) into the sciatic nerve resulted in transduction of up to 30% eGFP-positive cells of L4 DRG neurons in a dose dependant manner. More than 90% of transduced cells were small and medium sized neurons (< 700 μm2), predominantly colocalized with markers of nociceptive neurons, and had eGFP-positive central terminal fibers in the superficial lamina of the spinal cord dorsal horn. The efficiency and profile of transduction was independent of mouse genetic background. Intrathecal administration of rAAV2/6 gave the highest level of transduction (≈ 60%) and had a similar size profile and colocalization with nociceptive neurons. Intrathecal administration also transduced DRG neurons at cervical and thoracic levels and resulted in comparable levels of transduction in a mouse model for neuropathic pain. Subcutaneous and intramuscular delivery resulted in low levels of transduction in the L4 DRG. Likewise, delivery via tail vein injection resulted in relatively few eGFP-positive cells within the DRG, however, this transduction was observed at all vertebral levels and corresponded to large non-nociceptive cell types. We have found that rAAV2/6 is an efficient vector to deliver transgenes to nociceptive neurons in mice. Furthermore, the characterization of the transduction profile may facilitate gene transfer studies to dissect mechanisms behind neuropathic pain.
TL;DR: Cross-talk between nervous and immune systems occurs throughout the PNS during ALS disease progression, revealing a progressive innate and humoral immune response in peripheral nerves that is separate and distinct from spinal cord immune activation in ALS transgenic mice.
Abstract: During injury to the nervous system, innate immune cells mediate phagocytosis of debris, cytokine production, and axon regeneration. In the neuro-degenerative disease amyotrophic lateral sclerosis (ALS), innate immune cells in the CNS are activated. However, the role of innate immunity in the peripheral nervous system (PNS) has not been well defined. In this study, we characterized robust activation of CD169/CD68/Iba1+ macrophages throughout the PNS in mutant SOD1G93A and SOD1G37R transgenic mouse models of ALS. Macrophage activation occurred pre-symptomatically, and expanded from focal arrays within nerve bundles to a tissue-wide distribution following symptom onset. We found a striking dichotomy for immune cells within the spinal cord and PNS. Flow cytometry and GFP bone marrow chimeras showed that spinal cord microglia were mainly tissue resident derived, dendritic-like cells, whereas in peripheral nerves, the majority of activated macrophages infiltrated from the circulation. Humoral antibodies and complement localized to PNS tissue in tandem with macrophage recruitment, and deficiency in complement C4 led to decreased macrophage activation. Therefore, cross-talk between nervous and immune systems occurs throughout the PNS during ALS disease progression. These data reveal a progressive innate and humoral immune response in peripheral nerves that is separate and distinct from spinal cord immune activation in ALS transgenic mice.
TL;DR: In the present review, the anatomical and physiological features of the cnidarian nervous system and the interesting parallels in neurodevelopmental mechanisms between Cnidaria and Bilateria are discussed.
Abstract: Cnidarians are widely regarded as one of the first organisms in animal evolution possessing a nervous system Conventional histological and electrophysiological studies have revealed a considerable degree of complexity of the cnidarian nervous system Thanks to expressed sequence tags and genome projects and the availability of functional assay systems in cnidarians, this simple nervous system is now genetically accessible and becomes particularly valuable for understanding the origin and evolution of the genetic control mechanisms underlying its development In the present review, the anatomical and physiological features of the cnidarian nervous system and the interesting parallels in neurodevelopmental mechanisms between Cnidaria and Bilateria are discussed
Book•
01 Jan 2009
TL;DR: 1.1.
Abstract: 1. Introduction 2. Neuroanatomy by Dissection 3. Development of the Nervous System: Malformation 4. Cerebrospinal Fluid and Hydrocephalus 5. Lower Motor Neuron: Spinal 6. Lower Motor Neuron: General Somatic 7. Lower Motor Neuron: General Visceral Efferent System 8. Upper Motor Neuron 9. General Sensory Systems: * General Prioprioception-GP * General Somatic Afferent-GSA 10. Small Animal Spinal Cord Disease 11. Large Animal Spinal Cord Disease 12. Vestibular System: Special Proprioception (SP) 13. Cerebellum 14. Visual System 15. Auditory System: Special Somatic Afferent System 16. Visceral Afferent Systems 17. Non-Olfactory Rhinencephalon: Limbic System 18. Seizure Disorders: Narcolepsy 19. Diencephalon 20. The Neurologic Examination 21. Case Descriptions
TL;DR: It is found that satellite glial cell precursors are the primary phagocytic cells for apoptotic corpse removal in developing mouse dorsal root ganglia (DRG), and Jedi-1 and MEGF10 are identified as homologs of the invertebrate engulfment receptors Draper and CED-1 expressed in the glial precursor cells.
Abstract: During the development of peripheral ganglia, 50% of the neurons that are generated undergo apoptosis. How the massive numbers of corpses are removed is unknown. We found that satellite glial cell precursors are the primary phagocytic cells for apoptotic corpse removal in developing mouse dorsal root ganglia (DRG). Confocal and electron microscopic analysis revealed that glial precursors, rather than macrophages, were responsible for clearing most of the dead DRG neurons. Moreover, we identified Jedi-1, an engulfment receptor, and MEGF10, a purported engulfment receptor, as homologs of the invertebrate engulfment receptors Draper and CED-1 expressed in the glial precursor cells. Expression of Jedi-1 or MEGF10 in fibroblasts facilitated binding to dead neurons, and knocking down either protein in glial cells or overexpressing truncated forms lacking the intracellular domain inhibited engulfment of apoptotic neurons. Together, these results suggest a cellular and molecular mechanism by which neuronal corpses are culled during DRG development.
TL;DR: Draxin is a previously unknown chemorepulsive axon guidance molecule required for the development of spinal cord and forebrain commissures and is identified as a secreted protein that shares no homology with known guidance cues.
Abstract: Axon guidance proteins are critical for the correct wiring of the nervous system during development. Several axon guidance cues and their family members have been well characterized. More unidentified axon guidance cues are assumed to participate in the formation of the extremely complex nervous system. We identified a secreted protein, draxin, that shares no homology with known guidance cues. Draxin inhibited or repelled neurite outgrowth from dorsal spinal cord and cortical explants in vitro. Ectopically expressed draxin inhibited growth or caused misrouting of chick spinal cord commissural axons in vivo. draxin knockout mice showed defasciculation of spinal cord commissural axons and absence of all forebrain commissures. Thus, draxin is a previously unknown chemorepulsive axon guidance molecule required for the development of spinal cord and forebrain commissures.
TL;DR: In vivo experiments on the embryonic Drosophila nervous system show that vesicle clustering at the neuromuscular presynaptic terminal depends on mechanical tension within the axons, and suggest that neuromUScular synapses employ mechanical tension as a signal to modulate vesicles accumulation and synaptic plasticity.
Abstract: Memory and learning in animals are mediated by neurotransmitters that are released from vesicles clustered at the synapse. As a synapse is used more frequently, its neurotransmission efficiency increases, partly because of increased vesicle clustering in the presynaptic neuron. Vesicle clustering has been believed to result primarily from biochemical signaling processes that require the connectivity of the presynaptic terminal with the cell body, the central nervous system, and the postsynaptic cell. Our in vivo experiments on the embryonic Drosophila nervous system show that vesicle clustering at the neuromuscular presynaptic terminal depends on mechanical tension within the axons. Vesicle clustering vanishes upon severing the axon from the cell body, but is restored when mechanical tension is applied to the severed end of the axon. Clustering increases when intact axons are stretched mechanically by pulling the postsynaptic muscle. Using micro mechanical force sensors, we find that embryonic axons that have formed neuromuscular junctions maintain a rest tension of ≈1 nanonewton. If the rest tension is perturbed mechanically, axons restore the rest tension either by relaxing or by contracting over a period of ≈15 min. Our results suggest that neuromuscular synapses employ mechanical tension as a signal to modulate vesicle accumulation and synaptic plasticity.
TL;DR: It is found that Rheb is required for EGF-dependent mTOR activation in spinal cord astrocytes, whereas the Ras–MAP kinase pathway does not appear to be involved, andAstrocyte growth and E GF-dependent chemoattraction were inhibited by the mTOR-selective drug rapamycin.
Abstract: Astrocytes in the CNS respond to tissue damage by becoming reactive. They migrate, undergo hypertrophy, and form a glial scar that inhibits axon regeneration. Therefore, limiting astrocytic responses represents a potential therapeutic strategy to improve functional recovery. It was recently shown that the epidermal growth factor (EGF) receptor is upregulated in astrocytes after injury and promotes their transformation into reactive astrocytes. Furthermore, EGF receptor inhibitors were shown to enhance axon regeneration in the injured optic nerve and promote recovery after spinal cord injury. However, the signaling pathways involved were not elucidated. Here we show that in cultures of adult spinal cord astrocytes EGF activates the mTOR pathway, a key regulator of astrocyte physiology. This occurs through Akt-mediated phosphorylation of the GTPase-activating protein Tuberin, which inhibits Tuberin's ability to inactivate the small GTPase Rheb. Indeed, we found that Rheb is required for EGF-dependent mTOR activation in spinal cord astrocytes, whereas the Ras-MAP kinase pathway does not appear to be involved. Moreover, astrocyte growth and EGF-dependent chemoattraction were inhibited by the mTOR-selective drug rapamycin. We also detected elevated levels of activated EGF receptor and mTOR signaling in reactive astrocytes in vivo in an ischemic model of spinal cord injury. Furthermore, increased Rheb expression likely contributes to mTOR activation in the injured spinal cord. Interestingly, injured rats treated with rapamycin showed reduced signs of reactive gliosis, suggesting that rapamycin could be used to harness astrocytic responses in the damaged nervous system to promote an environment more permissive to axon regeneration.
01 Jan 2009
TL;DR: In this paper, the authors used a readily accessible human cell population, dental pulp progenitor/stem cells (DPSCs) that can differentiate into functionally active neurons given the appropriate environmental cues, and hypothesized that implanted DPSCs secrete factors that coordinate axon guidance within a receptive host nervous system.
Abstract: The human central nervous system has limited capacity for regeneration. Stem cell-based therapies may overcome this through cellular mechanisms of neural replacement and/or through molecular mechanisms, whereby secreted factors induce change in the host tissue. To investigate these mechanisms, we used a readily accessible human cell population, dental pulp progenitor/stem cells (DPSCs) that can differentiate into functionally active neurons given the appropriate environmental cues. We hypothesized that implanted DPSCs secrete factors that coordinate axon guidance within a receptive host nervous system. An avian embryonic model system was adapted to investigate axon guidance in vivo after transplantation of adult human DPSCs. Chemoattraction of avian trigeminal ganglion axons toward implanted DPSCs was mediated via the chemokine, CXCL12, also known as stromal cell-derived factor-1, and its receptor, CXCR4. These findings provide the first direct evidence that DPSCs may induce neuroplasticity within a receptive host nervous system. STEM CELLS 2009;27:2229–2237