Fernando Sepulveda - Academia.edu (original) (raw)

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Papers by Fernando Sepulveda

Research paper thumbnail of Simple Hadronic Cascade Simulations

Brazilian Journal of Physics, 2007

We obtain results for the average number of muons at sea level in a proton-initiated vertical atm... more We obtain results for the average number of muons at sea level in a proton-initiated vertical atmospheric cascade using a simple model of hadronic interactions based on the Hillas splitting algorithm. We study the muon yield at sea level as a function of the proton primary energy, varying the parameters of the interaction model in order to see the behavior of our results. We find that our results are in agreement with experimental data and with those of more sophisticated simulation models for some particular values of the model parameters.

Research paper thumbnail of Household Credit Markets During the Financial Crisis of 2008/2009

La serie de Documentos de Trabajo en versión PDF puede obtenerse gratis en la dirección electróni... more La serie de Documentos de Trabajo en versión PDF puede obtenerse gratis en la dirección electrónica: http://www.bcentral.cl/esp/estpub/estudios/dtbc. Existe la posibilidad de solicitar una copia impresa con un costo de 500siesdentrodeChileyUS500 si es dentro de Chile y US500siesdentrodeChileyUS12 si es para fuera de Chile. Las solicitudes se pueden hacer por fax: (56-2) 6702231 o a través de correo electrónico: bcch@bcentral.cl.

Research paper thumbnail of Changes in the apparent chloride permeability of Necturus enterocytes during the sodium-coupled transport of alanine

Biochimica Et Biophysica Acta-biomembranes, 1987

The membrane potential and intracellular CI-activity of Necturus enterocytes were measured with d... more The membrane potential and intracellular CI-activity of Necturus enterocytes were measured with double-barrelled ion-selective microelectrodes and apparent permeability coefficients (P a) for the apical membrane calculated from Ci--replacement experiments. In the presence of L°alanine in the mucosal solution an increase in Pa took place. It is proposed that this might reflect the activation of a CIconductance during active substrate transport.

Research paper thumbnail of Anti-homeostatic synaptic plasticity of glycine receptor function after chronic strychnine in developing cultured mouse spinal neurons

Journal of Neurochemistry, 2007

In this study, we describe a novel form of anti-homeostatic plasticity produced after culturing s... more In this study, we describe a novel form of anti-homeostatic plasticity produced after culturing spinal neurons with strychnine, but not bicuculline or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Strychnine caused a large increase in network excitability, detected as spontaneous synaptic currents and calcium transients. The calcium transients were associated with action potential firing and activation of γ-aminobutyric acid (GABAA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors as they were blocked by tetrodotoxin (TTX), bicuculline, and CNQX. After chronic blockade of glycine receptors (GlyRs), the frequency of synaptic transmission showed a significant enhancement demonstrating the phenomenon of anti-homeostatic plasticity. Spontaneous inhibitory glycinergic currents in treated cells showed a fourfold increase in frequency (from 0.55 to 2.4 Hz) and a 184% increase in average peak amplitude compared with control. Furthermore, the augmentation in excitability accelerated the decay time constant of miniature inhibitory post-synaptic currents. Strychnine caused an increase in GlyR current density, without changes in the apparent affinity. These findings support the idea of a post-synaptic action that partly explains the increase in synaptic transmission. This phenomenon of synaptic plasticity was blocked by TTX, an antibody against brain-derived neurotrophic factor (BDNF) and K252a suggesting the involvement of the neuronal activity-dependent BDNF-TrkB signaling pathway. These results show that the properties of GlyRs are regulated by the degree of neuronal activity in the developing network.

Research paper thumbnail of Synaptotoxicity of Alzheimer Beta Amyloid Can Be Explained by Its Membrane Perforating Property

PLOS One, 2010

The mechanisms that induce Alzheimer's disease (AD) are largely unknown thereby deterring the dev... more The mechanisms that induce Alzheimer's disease (AD) are largely unknown thereby deterring the development of diseasemodifying therapies. One working hypothesis of AD is that Ab excess disrupts membranes causing pore formation leading to alterations in ionic homeostasis. However, it is largely unknown if this also occurs in native brain neuronal membranes.

Research paper thumbnail of Sustained increase of Ca +2 oscillations after chronic TRPV1 receptor activation with capsaicin in cultured spinal neurons

Brain Research, 2008

Hyperalgesia and allodynia occur as a consequence of peripheral and central sensitization that fo... more Hyperalgesia and allodynia occur as a consequence of peripheral and central sensitization that follows sustained nociceptive activation. The cellular alterations associated to this state of nociceptive network hyperexcitability represent a form of neuronal plasticity, but they are not well understood because of its complexity in situ. In this study, after treating primary spinal neuron cultures with capsaicin (0.5-1 μM) for 48 h fluorimetric recordings were performed. The activation of TRPV1 receptors with capsaicin (0.5-1.0 μM) increased the frequency of calcium transients (0.03± 0.002 Hz vs. 0.05± 0.006 Hz, P b 0.05), mediated by AMPAergic transmission, as well as the percent of neurons with activity (37 ± 3% vs. 65± 4%, P b 0.05). The effect of capsaicin was long lasting and the neurons were found to be hyperfunctional and with increased levels of phosphorylated CREB (cAMP responsive element binding) even after 72 h of treatment with capsaicin (32 ± 5% vs. 52 ± 5%). The effect of capsaicin was blocked by capsazepine (1 μM), TTX (100 nM) and KN-62 (1 μM), but not by K252a (200 nM) or PD98059 (50 μM) indicating the involvement of TRPV1. The results suggest the participation of Ca 2+ , CaMKII and CREB on the prolonged enhancement of excitability following chronic exposure to capsaicin. Thus, it is likely that chronic TRPV1 activation is capable of inducing prolonged increases in neurotransmission mediated by glutamatergic receptors.

Research paper thumbnail of Alzheimer β-amyloid blocks epileptiform activity in hippocampal neurons

Molecular and Cellular Neuroscience, 2009

Several studies showed that hippocampal neurons respond with an increase in synaptic transmission... more Several studies showed that hippocampal neurons respond with an increase in synaptic transmission after chronic blockade of GABA A receptors with bicuculline, a neuroplastic phenomenon likely associated to epileptiform states. Here, we tested the effect of Aβ 1-40 oligomers/aggregates, believed to be involved in Alzheimer's Disease (AD) genesis, on this type of synaptic plasticity. In the presence of bicuculline, the frequency of miniature currents increased from 1.2 ± 0.4 Hz to 3.1 ± 0.6 Hz (n = 6, ⁎p b 0.05). Similarly, current amplitude increased from 45 ± 3 pA to 81 ± 11 pA (n = 5, ⁎p b 0.05). These effects were completely inhibited in the presence of Aβ 1-40 aggregates. Data suggest that Aβ aggregates exert their influence principally by blocking synaptic transmission and altering the transcriptional pathway associated with CREBp. In conclusion, neurons exposed to aggregated Aβ 1-40 showed a reduced level of neuronal plasticity and this suggests that they might be acting as anti-epileptiform modulators.

Research paper thumbnail of Synaptotoxicity of Alzheimer Beta Amyloid Can Be Explained by Its Membrane Perforating Property

PLOS One, 2010

The mechanisms that induce Alzheimer's disease (AD) are largely unknown thereby deterring the dev... more The mechanisms that induce Alzheimer's disease (AD) are largely unknown thereby deterring the development of diseasemodifying therapies. One working hypothesis of AD is that Ab excess disrupts membranes causing pore formation leading to alterations in ionic homeostasis. However, it is largely unknown if this also occurs in native brain neuronal membranes.

Research paper thumbnail of Aβ oligomers and fibrils instigate the release of excitatory amino acids from hippocampal neurons

Alzheimers & Dementia, 2010

Alzheimer's & Dementia: The Journal of the Alzheimer's Asso... more Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Volume 6, Issue 4, Pages S407, July 2010, Authors:Jordano Brito Moreira; Andrea Cristina Paula Lima; Theresa R. Bomfim; Fábio Figueiredo Oliveira; Fernando J. Sepúlveda; Fernando G. de Mello; Luis G. Aguayo ...

Research paper thumbnail of PoreForming Neurotoxin-Like Mechanism for Aβ Oligomer-Induced Synaptic Failure

Cortical and hippocampal synapse densities are reduced in Alzheimer’s disease (AD), and this stro... more Cortical and hippocampal synapse densities are reduced in Alzheimer’s disease (AD), and this strongly correlates with memory dysfunction. It is now believed that these changes in neuronal networking occur at the onset of AD and may lead to the neuronal loss displayed in later stages of the disease, which is characterized by severe cognitive and behavioral impairments. Mounting evidence indicates that amyloid-β (Aβ) oligomers are responsible for synaptic disconnections and neuronal death. One of the main consequences of Aβ oligomers interaction with neurons is an increase in intracellular Ca2+ concentration that could, when large enough, cause a marked alteration in ionic homeostasis. It has also been postulated that Ca2+ influx occurs when Aβ oligomers induce the opening of Ca2+ channels or the disruption of the plasma membrane. We recently found that the effects of Aβ oligomers on synaptic transmission are similar to pore-forming toxins, such as α-latrotoxin, a neurotoxin from the black widow spider. Here, we discuss evidence supporting a neurotoxin-like mechanism for the effects induced by Aβ oligomers on neuronal membranes, which could explain the alterations in the functionality of synapses in the central nervous system in AD that leads to major neurodegeneration with time of exposure to Aβ oligomers.

Research paper thumbnail of Regulation of glycinergic and GABAergic synaptogenesis by brain-derived neurotrophic factor in developing spinal neurons

Neuroscience, 2007

Brain-derived neurotrophic factor (BDNF) effects on the establishment of glycinergic and GABAergi... more Brain-derived neurotrophic factor (BDNF) effects on the establishment of glycinergic and GABAergic transmissions in mouse spinal neurons were examined using combined electrophysiological and calcium imaging techniques. BDNF (10 ng/ml) caused a significant acceleration in the onset of synaptogenesis without large effects on the survival of these neurons. Amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) associated to activation of glycine and GABA A receptors were augmented in neurons cultured with BDNF. The neurotrophin effect was blocked by long term tetrodotoxin (TTX) addition suggesting a dependence on neuronal activity. In addition, BDNF caused a significant increase in glycine-and GABA-evoked current densities that partly explains the increase in synaptic transmission. Presynaptic mechanisms were also involved in BDNF effects since triethylammonium(propyl)-4-(2-(4-dibutylamino-phenyl)vinyl)pyridinium (FM1-43) destaining with high K ؉ was augmented in neurons incubated with the neurotrophin. The effects of BDNF were mediated by receptor tyrosine kinase B (TrkB) and mitogen-activated protein kinase kinase (MEK) activation since culturing neurons with either (9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3=,2=,1=-kl] pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (K252a) or 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) blocked the augmentation in synaptic activity induced by the neurotrophin.

Research paper thumbnail of P3-432

Alzheimers & Dementia, 2006

Research paper thumbnail of Estimación multicriterio del costo de capital patrimonial* Multicriteria Estimated Cost of Equity Capital

Research paper thumbnail of Simple Hadronic Cascade Simulations

Brazilian Journal of Physics, 2007

We obtain results for the average number of muons at sea level in a proton-initiated vertical atm... more We obtain results for the average number of muons at sea level in a proton-initiated vertical atmospheric cascade using a simple model of hadronic interactions based on the Hillas splitting algorithm. We study the muon yield at sea level as a function of the proton primary energy, varying the parameters of the interaction model in order to see the behavior of our results. We find that our results are in agreement with experimental data and with those of more sophisticated simulation models for some particular values of the model parameters.

Research paper thumbnail of Household Credit Markets During the Financial Crisis of 2008/2009

La serie de Documentos de Trabajo en versión PDF puede obtenerse gratis en la dirección electróni... more La serie de Documentos de Trabajo en versión PDF puede obtenerse gratis en la dirección electrónica: http://www.bcentral.cl/esp/estpub/estudios/dtbc. Existe la posibilidad de solicitar una copia impresa con un costo de 500siesdentrodeChileyUS500 si es dentro de Chile y US500siesdentrodeChileyUS12 si es para fuera de Chile. Las solicitudes se pueden hacer por fax: (56-2) 6702231 o a través de correo electrónico: bcch@bcentral.cl.

Research paper thumbnail of Changes in the apparent chloride permeability of Necturus enterocytes during the sodium-coupled transport of alanine

Biochimica Et Biophysica Acta-biomembranes, 1987

The membrane potential and intracellular CI-activity of Necturus enterocytes were measured with d... more The membrane potential and intracellular CI-activity of Necturus enterocytes were measured with double-barrelled ion-selective microelectrodes and apparent permeability coefficients (P a) for the apical membrane calculated from Ci--replacement experiments. In the presence of L°alanine in the mucosal solution an increase in Pa took place. It is proposed that this might reflect the activation of a CIconductance during active substrate transport.

Research paper thumbnail of Anti-homeostatic synaptic plasticity of glycine receptor function after chronic strychnine in developing cultured mouse spinal neurons

Journal of Neurochemistry, 2007

In this study, we describe a novel form of anti-homeostatic plasticity produced after culturing s... more In this study, we describe a novel form of anti-homeostatic plasticity produced after culturing spinal neurons with strychnine, but not bicuculline or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Strychnine caused a large increase in network excitability, detected as spontaneous synaptic currents and calcium transients. The calcium transients were associated with action potential firing and activation of γ-aminobutyric acid (GABAA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors as they were blocked by tetrodotoxin (TTX), bicuculline, and CNQX. After chronic blockade of glycine receptors (GlyRs), the frequency of synaptic transmission showed a significant enhancement demonstrating the phenomenon of anti-homeostatic plasticity. Spontaneous inhibitory glycinergic currents in treated cells showed a fourfold increase in frequency (from 0.55 to 2.4 Hz) and a 184% increase in average peak amplitude compared with control. Furthermore, the augmentation in excitability accelerated the decay time constant of miniature inhibitory post-synaptic currents. Strychnine caused an increase in GlyR current density, without changes in the apparent affinity. These findings support the idea of a post-synaptic action that partly explains the increase in synaptic transmission. This phenomenon of synaptic plasticity was blocked by TTX, an antibody against brain-derived neurotrophic factor (BDNF) and K252a suggesting the involvement of the neuronal activity-dependent BDNF-TrkB signaling pathway. These results show that the properties of GlyRs are regulated by the degree of neuronal activity in the developing network.

Research paper thumbnail of Synaptotoxicity of Alzheimer Beta Amyloid Can Be Explained by Its Membrane Perforating Property

PLOS One, 2010

The mechanisms that induce Alzheimer's disease (AD) are largely unknown thereby deterring the dev... more The mechanisms that induce Alzheimer's disease (AD) are largely unknown thereby deterring the development of diseasemodifying therapies. One working hypothesis of AD is that Ab excess disrupts membranes causing pore formation leading to alterations in ionic homeostasis. However, it is largely unknown if this also occurs in native brain neuronal membranes.

Research paper thumbnail of Sustained increase of Ca +2 oscillations after chronic TRPV1 receptor activation with capsaicin in cultured spinal neurons

Brain Research, 2008

Hyperalgesia and allodynia occur as a consequence of peripheral and central sensitization that fo... more Hyperalgesia and allodynia occur as a consequence of peripheral and central sensitization that follows sustained nociceptive activation. The cellular alterations associated to this state of nociceptive network hyperexcitability represent a form of neuronal plasticity, but they are not well understood because of its complexity in situ. In this study, after treating primary spinal neuron cultures with capsaicin (0.5-1 μM) for 48 h fluorimetric recordings were performed. The activation of TRPV1 receptors with capsaicin (0.5-1.0 μM) increased the frequency of calcium transients (0.03± 0.002 Hz vs. 0.05± 0.006 Hz, P b 0.05), mediated by AMPAergic transmission, as well as the percent of neurons with activity (37 ± 3% vs. 65± 4%, P b 0.05). The effect of capsaicin was long lasting and the neurons were found to be hyperfunctional and with increased levels of phosphorylated CREB (cAMP responsive element binding) even after 72 h of treatment with capsaicin (32 ± 5% vs. 52 ± 5%). The effect of capsaicin was blocked by capsazepine (1 μM), TTX (100 nM) and KN-62 (1 μM), but not by K252a (200 nM) or PD98059 (50 μM) indicating the involvement of TRPV1. The results suggest the participation of Ca 2+ , CaMKII and CREB on the prolonged enhancement of excitability following chronic exposure to capsaicin. Thus, it is likely that chronic TRPV1 activation is capable of inducing prolonged increases in neurotransmission mediated by glutamatergic receptors.

Research paper thumbnail of Alzheimer β-amyloid blocks epileptiform activity in hippocampal neurons

Molecular and Cellular Neuroscience, 2009

Several studies showed that hippocampal neurons respond with an increase in synaptic transmission... more Several studies showed that hippocampal neurons respond with an increase in synaptic transmission after chronic blockade of GABA A receptors with bicuculline, a neuroplastic phenomenon likely associated to epileptiform states. Here, we tested the effect of Aβ 1-40 oligomers/aggregates, believed to be involved in Alzheimer's Disease (AD) genesis, on this type of synaptic plasticity. In the presence of bicuculline, the frequency of miniature currents increased from 1.2 ± 0.4 Hz to 3.1 ± 0.6 Hz (n = 6, ⁎p b 0.05). Similarly, current amplitude increased from 45 ± 3 pA to 81 ± 11 pA (n = 5, ⁎p b 0.05). These effects were completely inhibited in the presence of Aβ 1-40 aggregates. Data suggest that Aβ aggregates exert their influence principally by blocking synaptic transmission and altering the transcriptional pathway associated with CREBp. In conclusion, neurons exposed to aggregated Aβ 1-40 showed a reduced level of neuronal plasticity and this suggests that they might be acting as anti-epileptiform modulators.

Research paper thumbnail of Synaptotoxicity of Alzheimer Beta Amyloid Can Be Explained by Its Membrane Perforating Property

PLOS One, 2010

The mechanisms that induce Alzheimer's disease (AD) are largely unknown thereby deterring the dev... more The mechanisms that induce Alzheimer's disease (AD) are largely unknown thereby deterring the development of diseasemodifying therapies. One working hypothesis of AD is that Ab excess disrupts membranes causing pore formation leading to alterations in ionic homeostasis. However, it is largely unknown if this also occurs in native brain neuronal membranes.

Research paper thumbnail of Aβ oligomers and fibrils instigate the release of excitatory amino acids from hippocampal neurons

Alzheimers & Dementia, 2010

Alzheimer's & Dementia: The Journal of the Alzheimer's Asso... more Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Volume 6, Issue 4, Pages S407, July 2010, Authors:Jordano Brito Moreira; Andrea Cristina Paula Lima; Theresa R. Bomfim; Fábio Figueiredo Oliveira; Fernando J. Sepúlveda; Fernando G. de Mello; Luis G. Aguayo ...

Research paper thumbnail of PoreForming Neurotoxin-Like Mechanism for Aβ Oligomer-Induced Synaptic Failure

Cortical and hippocampal synapse densities are reduced in Alzheimer’s disease (AD), and this stro... more Cortical and hippocampal synapse densities are reduced in Alzheimer’s disease (AD), and this strongly correlates with memory dysfunction. It is now believed that these changes in neuronal networking occur at the onset of AD and may lead to the neuronal loss displayed in later stages of the disease, which is characterized by severe cognitive and behavioral impairments. Mounting evidence indicates that amyloid-β (Aβ) oligomers are responsible for synaptic disconnections and neuronal death. One of the main consequences of Aβ oligomers interaction with neurons is an increase in intracellular Ca2+ concentration that could, when large enough, cause a marked alteration in ionic homeostasis. It has also been postulated that Ca2+ influx occurs when Aβ oligomers induce the opening of Ca2+ channels or the disruption of the plasma membrane. We recently found that the effects of Aβ oligomers on synaptic transmission are similar to pore-forming toxins, such as α-latrotoxin, a neurotoxin from the black widow spider. Here, we discuss evidence supporting a neurotoxin-like mechanism for the effects induced by Aβ oligomers on neuronal membranes, which could explain the alterations in the functionality of synapses in the central nervous system in AD that leads to major neurodegeneration with time of exposure to Aβ oligomers.

Research paper thumbnail of Regulation of glycinergic and GABAergic synaptogenesis by brain-derived neurotrophic factor in developing spinal neurons

Neuroscience, 2007

Brain-derived neurotrophic factor (BDNF) effects on the establishment of glycinergic and GABAergi... more Brain-derived neurotrophic factor (BDNF) effects on the establishment of glycinergic and GABAergic transmissions in mouse spinal neurons were examined using combined electrophysiological and calcium imaging techniques. BDNF (10 ng/ml) caused a significant acceleration in the onset of synaptogenesis without large effects on the survival of these neurons. Amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) associated to activation of glycine and GABA A receptors were augmented in neurons cultured with BDNF. The neurotrophin effect was blocked by long term tetrodotoxin (TTX) addition suggesting a dependence on neuronal activity. In addition, BDNF caused a significant increase in glycine-and GABA-evoked current densities that partly explains the increase in synaptic transmission. Presynaptic mechanisms were also involved in BDNF effects since triethylammonium(propyl)-4-(2-(4-dibutylamino-phenyl)vinyl)pyridinium (FM1-43) destaining with high K ؉ was augmented in neurons incubated with the neurotrophin. The effects of BDNF were mediated by receptor tyrosine kinase B (TrkB) and mitogen-activated protein kinase kinase (MEK) activation since culturing neurons with either (9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3=,2=,1=-kl] pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (K252a) or 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) blocked the augmentation in synaptic activity induced by the neurotrophin.

Research paper thumbnail of P3-432

Alzheimers & Dementia, 2006

Research paper thumbnail of Estimación multicriterio del costo de capital patrimonial* Multicriteria Estimated Cost of Equity Capital