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glial cell membrane [keywords]
- Facilitation of Neuronal Responses by Intrinsic Default Mode Network Activity. [JOURNAL ARTICLE]
- Neural Comput 2014 Aug 22.:1-24.
Default mode network (DMN) shows intrinsic, high-level activity at rest. We tested a hypothesis proposed for its role in sensory information processing: Intrinsic DMN activity facilitates neural responses to sensory input. A neural network model, consisting of a sensory network (Nsen) and a DMN, was simulated. The Nsen contained cell assemblies. Each cell assembly comprised principal cells, GABAergic interneurons (Ia, Ib), and glial cells. We let the Nsen carry out a perceptual task: detection of sensory stimuli. During DMN activation, glial cells were hyperpolarized by Ia-to-glia circuitry, by which glial membrane transporters imported GABA molecules from the extracellular space and decreased ambient GABA concentration. Acting on extrasynaptic GABA receptors, the decrease in ambient GABA concentration reduced inhibitory current in a tonic manner. This depolarized principal cells below their firing threshold during the ongoing spontaneous time period and accelerated their reaction speed to a sensory stimulus. During the stimulus presentation period, the Nsen inhibited the DMN and caused DMN deactivation. The DMN deactivation made Nsen Ia cells cease firing, thereby stopping the glial membrane hyperpolarization, quitting the GABA import, returning to the basal ambient GABA level, and thus enhancing global inhibition. Notably, the stimulus-relevant P cell firing could be maintained when GABAergic gliotransmission via Ia-glia signaling worked, decreasing ambient GABA concentration around the stimulus-relevant P cells. This enabled the Nsen to reliably detect the stimulus. We suggest that intrinsic default model network activity may accelerate the reaction speed of the sensory network by modulating its ongoing-spontaneous activity in a subthreshold manner. Ambient GABA contributes to achieve an optimal ongoing spontaneous subthreshold neuronal state, in which GABAergic gliotransmission triggered by the intrinsic default model network activity may play an important role.
- Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. [Journal Article]
- Nat Rev Mol Cell Biol 2014 Aug 22; 15(9):577-90.
Membrane protrusions at the leading edge of cells, known as lamellipodia, drive cell migration in many normal and pathological situations. Lamellipodial protrusion is powered by actin polymerization, which is mediated by the actin-related protein 2/3 (ARP2/3)-induced nucleation of branched actin networks and the elongation of actin filaments. Recently, advances have been made in our understanding of positive and negative ARP2/3 regulators (such as the SCAR/WAVE (SCAR/WASP family verprolin-homologous protein) complex and Arpin, respectively) and of proteins that control actin branch stability (such as glial maturation factor (GMF)) or actin filament elongation (such as ENA/VASP proteins) in lamellipodium dynamics and cell migration. This Review highlights how the balance between actin filament branching and elongation, and between the positive and negative feedback loops that regulate these activities, determines lamellipodial persistence. Importantly, directional persistence, which results from lamellipodial persistence, emerges as a critical factor in steering cell migration.
- Membrane pathology and microglial activation of mice expressing membrane anchored or membrane released forms of Aβ and mutated human APP. [JOURNAL ARTICLE]
- Neuropathol Appl Neurobiol 2014 Aug 18.
Alzheimer's disease and the transmissible spongiform encephalopathies or prion diseases accumulate misfolded and aggregated forms of neuronal cell membrane proteins. Distinctive membrane lesions caused by the accumulation of disease-associated prion protein (PrP(d) ) are found in prion disease but morphological changes of membranes are not associated with Aβ in Alzheimer's disease. Membrane changes occur in all prion diseases where PrP(d) is attached to cell membranes by a glycosyl-phosphoinositol (GPI) anchor but are absent from transgenic mice expressing anchorless PrP(d) . Here we investigate whether GPI membrane attached Aβ may also cause prion-like membrane lesions.We used immunogold electron microscopy to determine the localization and pathology of Aβ accumulation in groups of transgenic mice expressing anchored or unanchored forms of Aβ or mutated human Alzheimer's precursor protein.GPI attached Aβ did not replicate the membrane lesions of PrP(d) . However, as with PrP(d) in prion disease, Aβ peptides derived from each transgenic mouse line initially accumulated on morphologically normal neurite membranes, elicited rapid glial recognition and neurite Aβ was transferred to attenuated microglial and astrocytic processes.GPI attachment of misfolded membrane proteins is insufficient to cause prion-like membrane lesions. Prion disease and murine Aβ amyloidosis both accumulate misfolded monomeric or oligomeric membrane proteins that are recognised by glial processes and acquire such misfolded proteins prior to their accumulation in the extracellular space. In contrast to prion disease where glial cells efficiently endocytose PrP(d) to endo-lysosomes, activated microglial cells in murine Aβ amyloidosis are not as efficient phagocytes.
- Tibolone protects T98G cells from glucose deprivation. [JOURNAL ARTICLE]
- J Steroid Biochem Mol Biol 2014 Jul 30.
The steroidal drug Tibolone is used for the treatment of climacteric symptoms and osteoporosis in post-menopausal women. Although Tibolone has been shown to exert neuroprotective actions after middle cerebral artery occlusion, its specific actions on glial cells have received very little attention. In the present study we have assessed whether Tibolone exerts protective actions in a human astrocyte cell model, the T98G cells, subjected to glucose deprivation. Our findings indicate that Tibolone decreases the effects of glucose deprivation on cell death, nuclear fragmentation, superoxide ion production, mitochondrial membrane potential, cytoplasmic calcium concentration and morphological parameters. These findings suggest that glial cells may participate in the neuroprotective actions of Tibolone in the brain.
- A Time Course Analysis of the Electrophysiological Properties of Neurons Differentiated from Human Induced Pluripotent Stem Cells (iPSCs). [Journal Article]
- PLoS One 2014; 9(7):e103418.
Many protocols have been designed to differentiate human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs) into neurons. Despite the relevance of electrophysiological properties for proper neuronal function, little is known about the evolution over time of important neuronal electrophysiological parameters in iPSC-derived neurons. Yet, understanding the development of basic electrophysiological characteristics of iPSC-derived neurons is critical for evaluating their usefulness in basic and translational research. Therefore, we analyzed the basic electrophysiological parameters of forebrain neurons differentiated from human iPSCs, from day 31 to day 55 after the initiation of neuronal differentiation. We assayed the developmental progression of various properties, including resting membrane potential, action potential, sodium and potassium channel currents, somatic calcium transients and synaptic activity. During the maturation of iPSC-derived neurons, the resting membrane potential became more negative, the expression of voltage-gated sodium channels increased, the membrane became capable of generating action potentials following adequate depolarization and, at day 48-55, 50% of the cells were capable of firing action potentials in response to a prolonged depolarizing current step, of which 30% produced multiple action potentials. The percentage of cells exhibiting miniature excitatory post-synaptic currents increased over time with a significant increase in their frequency and amplitude. These changes were associated with an increase of Ca2+ transient frequency. Co-culturing iPSC-derived neurons with mouse glial cells enhanced the development of electrophysiological parameters as compared to pure iPSC-derived neuronal cultures. This study demonstrates the importance of properly evaluating the electrophysiological status of the newly generated neurons when using stem cell technology, as electrophysiological properties of iPSC-derived neurons mature over time.
- Mitochondria-Targeted Catalase Reverts the Neurotoxicity of hSOD1G93A Astrocytes without Extending the Survival of ALS-Linked Mutant hSOD1 Mice. [Journal Article]
- PLoS One 2014; 9(7):e103438.
Dominant mutations in the Cu/Zn-superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the progressive loss of motor neurons. The molecular mechanism underlying the toxic gain-of-function of mutant hSOD1s remains uncertain. Several lines of evidence suggest that toxicity to motor neurons requires damage to non-neuronal cells. In line with this observation, primary astrocytes isolated from mutant hSOD1 over-expressing rodents induce motor neuron death in co-culture. Mitochondrial alterations have been documented in both neuronal and glial cells from ALS patients as well as in ALS-animal models. In addition, mitochondrial dysfunction and increased oxidative stress have been linked to the toxicity of mutant hSOD1 in astrocytes and neurons. In mutant SOD1-linked ALS, mitochondrial alterations may be partially due to the increased association of mutant SOD1 with the outer membrane and intermembrane space of the mitochondria, where it can affect several critical aspects of mitochondrial function. We have previously shown that decreasing glutathione levels, which is crucial for peroxide detoxification in the mitochondria, significantly accelerates motor neuron death in hSOD1G93A mice. Here we employed a catalase targeted to the mitochondria to investigate the effect of increased mitochondrial peroxide detoxification capacity in models of mutant hSOD1-mediated motor neuron death. The over-expression of mitochondria-targeted catalase improved mitochondrial antioxidant defenses and mitochondrial function in hSOD1G93A astrocyte cultures. It also reverted the toxicity of hSOD1G93A-expressing astrocytes towards co-cultured motor neurons, however ALS-animals did not develop the disease later or survive longer. Hence, while increased oxidative stress and mitochondrial dysfunction have been extensively documented in ALS, these results suggest that preventing peroxide-mediated mitochondrial damage alone is not sufficient to delay the disease.
- Signaling mechanisms and disrupted cytoskeleton in the diphenyl ditelluride neurotoxicity. [Journal Article]
- Oxid Med Cell Longev 2014.:458601.
Evidence from our group supports that diphenyl ditelluride (PhTe)2 neurotoxicity depends on modulation of signaling pathways initiated at the plasma membrane. The (PhTe)2-evoked signal is transduced downstream of voltage-dependent Ca(2+) channels (VDCC), N-methyl-D-aspartate receptors (NMDA), or metabotropic glutamate receptors activation via different kinase pathways (protein kinase A, phospholipase C/protein kinase C, mitogen-activated protein kinases (MAPKs), and Akt signaling pathway). Among the most relevant cues of misregulated signaling mechanisms evoked by (PhTe)2 is the cytoskeleton of neural cells. The in vivo and in vitro exposure to (PhTe)2 induce hyperphosphorylation/hypophosphorylation of neuronal and glial intermediate filament (IF) proteins (neurofilaments and glial fibrillary acidic protein, resp.) in different brain structures of young rats. Phosphorylation of IFs at specific sites modulates their association/disassociation and interferes with important physiological roles, such as axonal transport. Disrupted cytoskeleton is a crucial marker of neurodegeneration and is associated with reactive astrogliosis and apoptotic cell death. This review focuses the current knowledge and important results on the mechanisms of (PhTe)2 neurotoxicity with special emphasis on the cytoskeletal proteins and their differential regulation by kinases/phosphatases and Ca(2+)-mediated mechanisms in developmental rat brain. We propose that the disrupted cytoskeletal homeostasis could support brain damage provoked by this neurotoxicant.
- Nifedipine and nimodipine protect dopaminergic substantia nigra neurons against axotomy-induced cell death in rat vibrosections via modulating inflammatory responses. [JOURNAL ARTICLE]
- Brain Res 2014 Jul 16.
Neurodegeneration of cholinergic and dopaminergic neurons is a major hallmark in Alzheimer׳s or Parkinson׳s disease, respectively. A dysregulation in calcium homeostasis may be part of this process and counteracting calcium influx may have neuroprotective properties in both diseases. Therefore, we investigated the putative neuroprotective or neurotoxic activity of L-type calcium channel (LTCC) inhibitors on cholinergic and dopaminergic neurons in a rat organotypic vibrosection model. Sagittal or coronal vibrosections (200μm thick) of postnatal day 10 rats were cultured on 0.4μm semipermeable membranes for 2 weeks with 10ng/ml nerve growth factor (NGF) and/or glial-cell line derived neurotrophic factor (GDNF) to maintain survival of cholinergic or dopaminergic neurons, respectively. Thereafter, sections were incubated with 0.1, 1 or 10μM isradipine, nicardipine or verapamil for 2 weeks to explore cytotoxicity. Alternatively, in order to explore neuroprotective activity, vibrosections were incubated without growth factors but with isradipine or verapamil or with nicardipine, nimodipine or nifedipine from the beginning for 4 weeks. Our data show that all LTCC inhibitors exhibited no neurotoxic effect on cholinergic and dopaminergic neurons. Further, LTCC inhibitors did not have any neuroprotective activity on cholinergic neurons. However, nimodipine and nifedipine significantly enhanced the survival of dopaminergic substantia nigra (SN) but not ventral tegmental area (VTA) neurons, while nicardipine, isradipine and verapamil had no effect. Nifedipine (and more potently GDNF) reduced inflammatory cytokines (macrophage inflammatory protein-2, tumor necrosis factor-α), but did not influence oxidative stress or caspase-3 activity and did not interfere with iron-mediated overload. Our data show that nifedipine and nimodipine are very potent to enhance the survival of axotomized SN neurons, possibly influencing inflammatory processes.
- Neuron-Glia Interactions through the Heartless FGF Receptor Signaling Pathway Mediate Morphogenesis of Drosophila Astrocytes. [JOURNAL ARTICLE]
- Neuron 2014 Jul 16; 83(2):388-403.
Astrocytes are critically important for neuronal circuit assembly and function. Mammalian protoplasmic astrocytes develop a dense ramified meshwork of cellular processes to form intimate contacts with neuronal cell bodies, neurites, and synapses. This close neuron-glia morphological relationship is essential for astrocyte function, but it remains unclear how astrocytes establish their intricate morphology, organize spatial domains, and associate with neurons and synapses in vivo. Here we characterize a Drosophila glial subtype that shows striking morphological and functional similarities to mammalian astrocytes. We demonstrate that the Fibroblast growth factor (FGF) receptor Heartless autonomously controls astrocyte membrane growth, and the FGFs Pyramus and Thisbe direct astrocyte processes to ramify specifically in CNS synaptic regions. We further show that the shape and size of individual astrocytes are dynamically sculpted through inhibitory or competitive astrocyte-astrocyte interactions and Heartless FGF signaling. Our data identify FGF signaling through Heartless as a key regulator of astrocyte morphological elaboration in vivo.
- RCAN1 Regulates Mitochondrial Function and Increases Susceptibility to Oxidative Stress in Mammalian Cells. [Journal Article]
- Oxid Med Cell Longev 2014.:520316.
Mitochondria are the primary site of cellular energy generation and reactive oxygen species (ROS) accumulation. Elevated ROS levels are detrimental to normal cell function and have been linked to the pathogenesis of neurodegenerative disorders such as Down's syndrome (DS) and Alzheimer's disease (AD). RCAN1 is abundantly expressed in the brain and overexpressed in brain of DS and AD patients. Data from nonmammalian species indicates that increased RCAN1 expression results in altered mitochondrial function and that RCAN1 may itself regulate neuronal ROS production. In this study, we have utilized mice overexpressing RCAN1 (RCAN1(ox)) and demonstrate an increased susceptibility of neurons from these mice to oxidative stress. Mitochondria from these mice are more numerous and smaller, indicative of mitochondrial dysfunction, and mitochondrial membrane potential is altered under conditions of oxidative stress. We also generated a PC12 cell line overexpressing RCAN1 (PC12(RCAN1)). Similar to RCAN1(ox) neurons, PC12(RCAN1) cells have an increased susceptibility to oxidative stress and produce more mitochondrial ROS. This study demonstrates that increasing RCAN1 expression alters mitochondrial function and increases the susceptibility of neurons to oxidative stress in mammalian cells. These findings further contribute to our understanding of RCAN1 and its potential role in the pathogenesis of neurodegenerative disorders such as AD and DS.