79 research outputs found

    A unique role for Kv3 voltage-gated potassium channels in starburst amacrine cell signaling in mouse retina.

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    Direction-selective retinal ganglion cells show an increased activity evoked by light stimuli moving in the preferred direction. This selectivity is governed by direction-selective inhibition from starburst amacrine cells occurring during stimulus movement in the opposite or null direction. To understand the intrinsic membrane properties of starburst cells responsible for direction-selective GABA release, we performed whole-cell recordings from starburst cells in mouse retina. Voltage-clamp recordings revealed prominent voltage-dependent K(+) currents. The currents were mostly blocked by 1 mm TEA, activated rapidly at voltages more positive than -20 mV, and deactivated quickly, properties reminiscent of the currents carried by the Kv3 subfamily of K+ channels. Immunoblots confirmed the presence of Kv3.1 and Kv3.2 proteins in retina and immunohistochemistry revealed their expression in starburst cell somata and dendrites. The Kv3-like current in starburst cells was absent in Kv3.1-Kv3.2 knock-out mice. Current-clamp recordings showed that the fast activation of the Kv3 channels provides a voltage-dependent shunt that limits depolarization of the soma to potentials more positive than -20 mV. This provides a mechanism likely to contribute to the electrical isolation of individual starburst cell dendrites, a property thought essential for direction selectivity. This function of Kv3 channels differs from that in other neurons where they facilitate high-frequency repetitive firing. Moreover, we found a gradient in the intensity of Kv3.1b immunolabeling favoring proximal regions of starburst cells. We hypothesize that this Kv3 channel gradient contributes to the preference for centrifugal signal flow in dendrites underlying direction-selective GABA release from starburst amacrine cell

    Known by the company we keep: `Triadic influence' as a proxy for compatibility in social relationships

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    Networks of social interactions are the substrate upon which civilizations are built. Often, we create new bonds with people that we like or feel that our relationships are damaged through the intervention of third parties. Despite their importance and the huge impact that these processes have in our lives, quantitative scientific understanding of them is still in its infancy, mainly due to the difficulty of collecting large datasets of social networks including individual attributes. In this work, we present a thorough study of real social networks of 13 schools, with more than 3,000 students and 60,000 declared positive and negative relations, including tests for personal traits of all the students. We introduce a metric -- the `triadic influence' -- that measures the influence of nearest-neighbors in the relationships of their contacts. We use neural networks to predict the relationships and to extract the probability that two students are friends or enemies depending on their personal attributes or the triadic influence. We alternatively use a high-dimensional embedding of the network structure to also predict the relationships. Remarkably, the triadic influence (a simple one-dimensional metric) achieves the highest accuracy at predicting the relationship between two students. We postulate that the probabilities extracted from the neural networks -- functions of the triadic influence and the personalities of the students -- control the evolution of real social networks, opening a new avenue for the quantitative study of these systems

    Complex -Glycans Influence the Spatial Arrangement of Voltage Gated Potassium Channels in Membranes of Neuronal-Derived Cells

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    The intrinsic electrical properties of a neuron depend on expression of voltage gated potassium (Kv) channel isoforms, as well as their distribution and density in the plasma membrane. Recently, we showed that N-glycosylation site occupancy of Kv3.1b modulated its placement in the cell body and neurites of a neuronal-derived cell line, B35 neuroblastoma cells. To extrapolate this mechanism to other N-glycosylated Kv channels, we evaluated the impact of N-glycosylation occupancy of Kv3.1a and Kv1.1 channels. Western blots revealed that wild type Kv3.1a and Kv1.1 α-subunits had complex and oligomannose N-glycans, respectively, and that abolishment of the N-glycosylation site(s) generated Kv proteins without N-glycans. Total internal reflection fluorescence microscopy images revealed that N-glycans of Kv3.1a contributed to its placement in the cell membrane while N-glycans had no effect on the distribution of Kv1.1. Based on particle analysis of EGFP-Kv proteins in the adhered membrane, glycosylated forms of Kv3.1a, Kv1.1, and Kv3.1b had differences in the number, size or density of Kv protein clusters in the cell membrane of neurites and cell body of B35 cells. Differences were also observed between the unglycosylated forms of the Kv proteins. Cell dissociation assays revealed that cell-cell adhesion was increased by the presence of complex N-glycans of Kv3.1a, like Kv3.1b, whereas cell adhesion was similar in the oligomannose and unglycosylated Kv1.1 subunit containing B35 cells. Our findings provide direct evidence that N-glycans of Kv3.1 splice variants contribute to the placement of these glycoproteins in the plasma membrane of neuronal-derived cells while those of Kv1.1 were absent. Further when the cell membrane distribution of the Kv channel was modified by N-glycans then the cell-cell adhesion properties were altered. Our study demonstrates that N-glycosylation of Kv3.1a, like Kv3.1b, provides a mechanism for the distribution of these proteins to the cell body and outgrowths and thereby can generate different voltage-dependent conductances in these membranes

    Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice

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    Background: Alzheimer’s disease (AD) brain shows an ongoing inflammatory condition and non-steroidal antiinflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and antiinflammatory agents with therapeutic potential. Methods: We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months) on inflammatory and cognitive parameters, and on 18F-fluoro-deoxyglucose (18FDG) uptake by positron emission tomography (PET). Results: Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased 18FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-a mRNA expression found in the AD model. Increased cortical b-amyloid (Ab) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Ab transport across choroid plexus cells in vitro. Conclusions: In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Ab clearanceThis work was supported by the Spanish Ministry of Science and Technology (SAF 2005-02845 to M.L.C). A.M.M-M. was recipient a fellowship from the Ministry of Education and Scienc

    Antidepressants and Changes in Concentration of Endocannabinoids and N-Acylethanolamines in Rat Brain Structures

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    The endocannabinoid (eCB) system has recently been implicated in both the pathogenesis of depression and the action of antidepressants. Here, we investigated the effect of acutely or chronically administering antidepressants [imipramine (IMI) (15 mg/kg), escitalopram (ESC) (10 mg/kg), and tianeptine (10 mg/kg)] on the levels of both eCBs [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] and N-acylethanolamines (NAEs) [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)] in various rat brain regions. We also examined the ability of the acute and chronic administration of N-acetylcysteine (NAC) (a mucolytic drug; 100 mg/kg) or URB597 (a fatty acid amide hydrolase inhibitor; 0.3 mg/kg), which have both elicited antidepressant activity in preclinical studies, to affect eCB and NAE levels. Next, we determined whether the observed effects are stable 10 days after the chronic administration of these drugs was halted. We report that the chronic administration of all investigated drugs increased AEA levels in the hippocampus and also increased both AEA and 2-AG levels in the dorsal striatum. NAE levels in limbic regions also increased after treatment with IMI (PEA/OEA), ESC (PEA), and NAC (PEA/OEA). Removing chronic ESC treatment for 10 days affected eCB and NAE levels in the frontal cortex, hippocampus, dorsal striatum, and cerebellum, while a similar tianeptine-free period enhanced accumbal NAE levels. All other drugs maintained their effects after the 10-day washout period. Therefore, the eCB system appears to play a significant role in the mechanism of action of clinically effective and potential antidepressants and may serve as a target for drug design and discovery

    Competing for congestible goods: experimental evidence on parking choice

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    Congestible goods describe situations in which a group of people share or use a public good that becomes congested or overexploited when demand is low. We study experimentally a congestible goods problem of relevance for parking design, namely how people choose between a convenient parking lot with few spots and a less convenient one with unlimited space. We find that the Nash equilibrium predicts reasonably well the competition for the convenient parking when it has few spots, but not when it has more availability. We then show that the Rosenthal equilibrium, a bounded-rational approach, is a better description of the experimental results accounting for the randomness in the decision process. We introduce a dynamical model that shows how Rosenthal equilibria can be approached in a few rounds of the game. Our results give insights on how to deal with parking problems such as the design of parking lots in central locations in cities and open the way to better understand similar congestible goods problems in other contexts. © 2020, The Author(s)

    Competing for congestible goods: experimental evidence on parking choice

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    Congestible goods describe situations in which a group of people share or use a public good that becomes congested or overexploited when demand is low. We study experimentally a congestible goods problem of relevance for parking design, namely how people choose between a convenient parking lot with few spots and a less convenient one with unlimited space. We find that the Nash equilibrium predicts reasonably well the competition for the convenient parking when it has few spots, but not when it has more availability. We then show that the Rosenthal equilibrium, a bounded-rational approach, is a better description of the experimental results accounting for the randomness in the decision process. We introduce a dynamical model that shows how Rosenthal equilibria can be approached in a few rounds of the game. Our results give insights on how to deal with parking problems such as the design of parking lots in central locations in cities and open the way to better understand similar congestible goods problems in other contexts
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