DSpace Angular :: Browsing by Author "Cerpa Nebott, Waldo Francisco"

Browsing by Author "Cerpa Nebott, Waldo Francisco"

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Adolescent Binge Alcohol Exposure Affects the Brain Function Through Mitochondrial Impairment
(2018) Tapia-Rojas, Cheril; Carvajal Cachaña, Francisco Javier; Mira, Rodrigo G.; Arce, Camila; Manuel Lerma-Cabrera, Jose; Orellana Roca, Juan Andrés; Cerpa Nebott, Waldo Francisco; Quintanilla, Rodrigo A.
Age-related NMDA signaling alterations in SOD2 deficient mice
(2018) Carvajal Cachaña, Francisco Javier; Mira, Rodrigo G.; Rovegno Echavarria, Maxiliano; Minniti, Alicia N.; Cerpa Nebott, Waldo Francisco
Alcohol consumption during adolescence alters the hippocampal response to traumatic brain injury
(2020) Mira, Rodrigo G.; Lira, Matías; Quintanilla, Rodrigo A.; Cerpa Nebott, Waldo Francisco
Binge drinking is the consumption of large volumes of alcohol in short periods and exerts its effects on the central nervous system, including the hippocampus. We have previously shown that binge drinking alters mitochondrial dynamics and induces neuroinflammation in the hippocampus of adolescent rats. Mild traumatic brain injury (mTBI), is regularly linked to alcohol consumption and share mechanisms of brain damage. In this context, we hypothesized that adolescent binge drinking could prime the development of brain damage generated by mTBI. We found that alcohol binge drinking induced by the “drinking in the dark” (DID) paradigm increases oxidative damage and astrocyte activation in the hippocampus of adolescent mice. Interestingly, adolescent animals submitted to DID showed decreased levels of mitofusin 2 that controls mitochondrial dynamics. When mTBI was evaluated as a second challenge, hippocampi from animals previously submitted to DID showed a reduction in dendritic spine number and a different spine profile. Mitochondrial performance could be compromised by alterations in mitochondrial fission in DID-mTBI animals. These data suggest that adolescent alcohol consumption can modify the progression of mTBI pathophysiology. We propose that mitochondrial impairment and oxidative damage could act as priming factors, modifying predisposition against mTBI effects.
Alcohol consumption during adolescence: A link between mitochondrial damage and ethanol brain intoxication
(2017) Tapia, C.; Mira, R.; Torres, A.; Jara, C.; Pérez, M.; Vergara, E.; Cerpa Nebott, Waldo Francisco; Quintanilla Gómez, Rodrigo Arthur
Alcohol impairshippocampal function:FromNMDAreceptorsynaptic transmissiontomitochondrial function
(2019) Mira, Rodrigo G.; Tapia Rojas, Cheril; Pérez, María José; Jara, Claudia; Vergara, Erick H.; Quintanilla, Rodrigo A.; Cerpa Nebott, Waldo Francisco
Many studies have reported that alcohol produces harmful effects on several brain structures, including the hippocampus, in both rodents and humans. The hippocampus is one of the most studied areas of the brain due to its function in learning and memory, and a lot of evidence suggests that hippocampal failure is responsible for the cognitive loss present in individuals with recurrent alcohol consumption. Mitochondria are organelles that generate the energy needed for the brain to maintain neuronal communication, and their functional failure is considered a mediator of the synaptic dysfunction induced by alcohol. In this review, we discuss the mechanisms of how alcohol exposure affects neuronal communication through the impairment of glutamate receptor (NMDAR) activity, neuroinflammatory events and oxidative damage observed after alcohol exposure, all processes under the umbrella of mitochondrial function. Finally, we discuss the direct role of mitochondrial dysfunction mediating cognitive and memory decline produced by alcohol exposure and their consequences associated with neurodegeneration.
Amyloid-beta oligomers synaptotoxicity: The emerging role of epha4/c-Abl signaling in Alzheimer's disease
(2018) Vargas, L. M.; Cerpa Nebott, Waldo Francisco; Munoz, F. J.; Zanlungo Matsuhiro, Silvana; Álvarez Rojas, Alejandra
Amyloid-beta Peptide Fibrils Induce Nitro-Oxidative Stress in Neuronal Cells
(2010) Ill-Raga, G.; Godoy Zeballos, Juan Alejandro; Belmar Lucero, Sebastián Antoni; Cerpa Nebott, Waldo Francisco
Andrographolide reduces cognitive impairment in young and mature AÎ²PPswe/PS-1 mice
(2014) Serrano, F. G.; Tapia-Rojas, Cheril; Carvajal, F. J.; Hancke, J.; Cerpa Nebott, Waldo Francisco; Inestrosa Cantín, Nibaldo
Astroglial gliotransmitters released via Cx43 hemichannels regulate NMDAR-dependent transmission and short-term fear memory in the basolateral amygdala
(2022) Linsambarth, Sergio; Carvajal Cachaña, Francisco Javier; Moraga Amaro, Rodrigo; Mendez, Luis; Tamburini, Giovanni; Jimenez, Ivanka; Antonio Verdugo, Daniel; Gomez, Gonzalo, I; Jury, Nur; Martinez, Pablo; van Zundert, Brigitte; Varela Nallar, Lorena; Retamal, Mauricio A.; Martin, Claire; Altenberg, Guillermo A.; Fiori, Mariana C.; Cerpa Nebott, Waldo Francisco; Orellana Roca, Juan Andrés; Stehberg, Jimmy
Astrocytes release gliotransmitters via connexin 43 (Cx43) hemichannels into neighboring synapses, which can modulate synaptic activity and are necessary for fear memory consolidation. However, the gliotransmitters released, and their mechanisms of action remain elusive. Here, we report that fear conditioning training elevated Cx43 hemichannel activity in astrocytes from the basolateral amygdala (BLA). The selective blockade of Cx43 hemichannels by microinfusion of TAT-Cx43L2 peptide into the BLA induced memory deficits 1 and 24 h after training, without affecting learning. The memory impairments were prevented by the co-injection of glutamate and D-serine, but not by the injection of either alone, suggesting a role for NMDA receptors (NMDAR). The incubation with TAT-Cx43L2 decreased NMDAR-mediated currents in BLA slices, effect that was also prevented by the addition of glutamate and D-serine. NMDARs in primary neuronal cultures were unaffected by TAT-Cx43L2, ruling out direct effects of the peptide on NMDARs. Finally, we show that D-serine permeates through purified Cx43 hemichannels reconstituted in liposomes. We propose that the release of glutamate and D-serine from astrocytes through Cx43 hemichannels is necessary for the activation of post-synaptic NMDARs during training, to allow for the formation of short-term and subsequent long-term memory, but not for learning per se.
Binge-like Alcohol Administration Alters Decision Making in an Adolescent Rat Model: Role of N-Methyl-D-Aspartate Receptor Signaling
(2023) Arce Olave, Camila Raquel; Mira Guzmán, Rodrigo Andrés; Lira Mendieta, Matías Sebastián; Cerpa Nebott, Waldo Francisco
Alcohol is one of the most used legal drugs abused worldwide, and its consumption is associated with high mortality and morbidity rates. There is an increasing concern about the starting age of consumption of this drug since it has become evident that it is at younger ages. The so-called “pattern of consumption by binge” corresponds to ingesting large amounts of alcohol in a short period and is the most popular among young people. Previous studies show that alcohol causes damage in different areas, such as the hippocampus, hypothalamus, and prefrontal cortex, and adolescents are more susceptible to alcohol toxicity. Alcohol inhibits the membrane glutamate receptor, NMDA-type glutamate receptors (NMDAR). Using a binge-like alcohol administration protocol in adolescent rats (PND25), we investigate decision making through the attentional set-shifting test (ASST) and alterations in the NMDAR signaling in related areas. We observe an impairment in executive function without alterations in NMDAR abundance. However, binge alcohol changes NMDAR signaling and decreases quantity in the synapse, mainly in the hippocampus and hypothalamus. We suggest that prefrontal cortex impairment could arise from damaged connections with the hippocampus and hypothalamus, affecting the survival pathway and memory and learning process.
Building a Bridge Between NMDAR‑Mediated Excitotoxicity and Mitochondrial Dysfunction in Chronic and Acute Diseases
(2021) Mira, Rodrigo G.; Cerpa Nebott, Waldo Francisco
Glutamate is the major excitatory neurotransmitter in the brain, and it is widely accepted to play a role in synaptic plasticity and excitotoxic cell death. Glutamate binds to several receptors, including ionotropic N-methyl-D-Aspartate receptor (NMDAR), which is essential in synaptic plasticity and excitotoxicity. This receptor is a calcium channel that is located in synaptic and extrasynaptic sites, triggering different signalling cascades in each case. The calcium entry through extrasynaptic NMDARs is linked to calcium overload in the mitochondria in neurons in vitro. The mitochondria, besides their role in ATP production in the cell, participate in calcium homeostasis, acting as a buffering organelle. Disruption of mitochondrial calcium homeostasis has been linked to neuronal death either by triggering apoptosis or driven by the opening of the mitochondrial transition pore. These cell-death mechanisms contribute to the pathophysiology of diverse diseases such as neurodegenerative Alzheimer’s disease or Parkinson’s disease, and acute neuropathological conditions such as stroke or traumatic brain injury. In this review, we will address the available evidence that positions the mitochondria as an essential organelle in the control of calcium-mediated toxicity, highlighting its role from the perspective of specific NMDAR signalling microdomains at the level of the central synapse.
Exo70 intracellular redistribution after repeated mild traumatic brain injury
(2021) Lira Mendieta, Matías Sebastián; Zamorano, Pedro; Cerpa Nebott, Waldo Francisco
Abstract Background Exo70 is a subunit of the greater exocyst complex, a collection of proteins that oversees cellular membrane addition and polarized exocytosis by acting as a tethering intermediate between the plasma membrane and newly synthesized secretory vesicles. Although Exo70 function has been implicated in several developmental events including cytokinesis and the establishment of cell polarity, its role in neuropathologies is poorly understood. On the other hand, traumatic brain injury is the result of mechanical external force including contusion, fast acceleration, and expansive waves that produce temporal or permanent cognitive damage and triggers physical and psychosocial alterations including headache, memory problems, attention deficits, difficulty thinking, mood swings, and frustration. Traumatic brain injury is a critical health problem on a global scale, constituting a major cause of deaths and disability among young adults. Trauma-related cellular damage includes redistribution of N-methyl-D-aspartate receptors outside of the synaptic compartment triggering detrimental effects to neurons. The exocyst has been related to glutamate receptor constitutive trafficking/delivery towards synapse as well. This work examines whether the exocyst complex subunit Exo70 participates in traumatic brain injury and if it is redistributed among subcellular compartments Results Our analysis shows that Exo70 expression is not altered upon injury induction. By using subcellular fractionation, we determined that Exo70 is redistributed from microsomes fraction into the synaptic compartment after brain trauma. In the synaptic compartment, we also show that the exocyst complex assembly and its interaction with GluN2B are increased. Finally, we show that the Exo70 pool that is redistributed comes from the plasma membrane. Conclusions The present findings position Exo70 in the group of proteins that could modulate GluN2B synaptic availability in acute neuropathology like a traumatic brain injury. By acting as a nucleator factor, Exo70 is capable of redirecting the ensembled complex into the synapse. We suggest that this redistribution is part of a compensatory mechanism by which Exo70 is able to maintain GluN2B partially on synapses. Hence, reducing the detrimental effects associated with TBI pathophysiology.
Exo70 involvement on NMDAR dynamics in traumatic brain injury
(2021) Lira Mendieta, Matías Sebastián; Cerpa Nebott, Waldo Francisco; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas
El correcto funcionamiento de la sinapsis es fundamental para mantener la estabilidad neuronal. En neuropatologías como la lesión cerebral traumática (TBI), la sinapsis se altera o destruye. TBI es una condición que posee una alta incidencia a nivel mundial y es una causa importante de muertes y discapacidad. TBI se caracteriza por cambios de presión intracraneal debido a fuerzas de aceleración inducidas por el golpe, lo que genera un daño primario a nivel de tejido. El daño secundario posterior puede durar por semanas o meses, incluso años dependiendo de la gravedad del trauma. Este daño secundario es en parte mediado por glutamato al estimular receptores NMDA extrasinápticos, lo que desencadena una pérdida de función sináptica y por consiguiente alteración de conductas cognitivas y sociales. El daño mediado por el derrame de glutamato provoca una redistribución de receptores N-methyl-D-aspartic acid (NMDA) hacia sitios extrasinápticos, lo que potenciaría el daño generado por el glutamato extrasináptico. Uno de los componentes asociados a tráfico, exocitosis y mantención de los receptores de glutamato en la sinapsis es el exocisto. El exocisto es un complejo multiproteico constituido por 8 proteínas encargado de la exocitosis de membrana basolateral y de crecimiento de neuritas, así como también del tráfico y exocitosis de receptores de glutamato. A su vez, el exocisto ha sido relacionado a la disponibilidad basal de receptores de glutamato en la sinapsis y por lo tanto regula el umbral de activación de estos. A pesar de que se conoce bastante sobre el complejo exocisto a nivel celular, existe poca información que relacione al exocisto con neuropatologías. Nuestra hipótesis de trabajo es que Exo70 promueve la disponibilidad y señalización sináptica del receptor NMDA en respuesta a trauma cerebral inducido por golpe, manteniendo así procesos cognitivos. Para poner a prueba esta hipótesis se utilizó un modelo de trauma leve provocado por golpes repetitivos en ratones. Nuestros resultados demuestran que Exo70 es redistribuido hacia la sinapsis en condición TBI, donde el ensamblaje del complejo se incrementa y la interacción con GluN2B se ve favorecida. En esta tesis se logró la sobreexpresión de Exo70 en la región CA1 del hipocampo dorsal previo a la inducción de TBI, lo que nos permitió realizar ensayos conductuales, electrofisiológicos y bioquímicos que responden a la evaluación de la disponibilidad de receptores NMDA en la sinapsis. En estos experimentos encontramos que la previa sobreexpresión de Exo70 protege contra el deterioro cognitivo, acompañado de la estabilización de la transmisión glutamatérgica basal y la potenciación a largo plazo en hipocampo. Finalmente, GluN2B permanece en la sinapsis cuando Exo70 es sobre expresado, promoviendo así la señalización intracelular asociada a receptores NMDA sinápticos. Estos hallazgos revelan el papel que cumple Exo70 en la dinámica intracelular de receptores NMDA en condición de trauma cerebral y sugieren que Exo70 podría ser parte de la maquinaria de distribución sináptica de estos receptores en otras neuropatologías.
Exo70 protects against memory and synaptic impairments following mild traumatic brain injury
(2023) Lira, Matias; Abarca, Jorge; Mira, Rodrigo G.; Zamorano, Pedro; Cerpa Nebott, Waldo Francisco
Mild traumatic brain injury (mTBI) is damage to the brain due to external forces. It is the most frequent form of brain trauma and a leading cause of disability in young adults. Hippocampal glutamatergic transmission and synaptic plasticity are impaired after mTBI, and NMDA receptors play critical in these functions. The Exocyst is a vesicle tethering complex implicated in the trafficking of glutamate receptors. We have previously shown that Exo70, a critical exocyst's subunit, redistributes in the synapse and increases its interaction with GluN2B in response to mTBI, suggesting a role in the distribution of the GluN2B subunit of NMDARs from synaptic to extrasynaptic membranes. We tested whether Exo70 could prevent NMDAR depletion from the synapse and limit mTBI pathology. To this end, we used a modified Maryland's model of mTBI in mice overexpressing Exo70 in CA1 pyramidal neurons through a lentiviral vector transduction. We showed that after mTBI, the overexpression of Exo70 prevented the cognitive impairment observed in mice infected with a control vector using the Morris' water maze paradigm. Following these findings, mice overexpressing Exo70 showed basal and NMDAR-dependent hippocampal synaptic transmission comparable to sham animals, preventing the deterioration induced by mTBI. Long-term potentiation, abundant synaptic GluN2B-containing NMDARs, and downstream signaling effectors showed that Exo70 overexpression prevented the mTBI-induced alterations. Our findings revealed a crucial role of Exo70 in NMDAR trafficking to the synapse and suggested that the Exocyst complex may be a critical component of the basal machinery that regulates NMDAR distribution in health and disease.
Genetic ablation of tau improves mitochondrial function and cognitive abilities in the hippocampus
(2018) Jara, Claudia; Aránguiz, Alejandra; Cerpa Nebott, Waldo Francisco; Tapia-Rojas, Cheril; Quintanilla, Rodrigo A.
Heavy Alcohol Exposure Activates Astroglial Hemichannels and Pannexons in the Hippocampus of Adolescent Rats : Effects on Neuroinflammation and Astrocyte Arborization
(2018) Gomez, Gonzalo I.; Falcon, Romina V.; Maturana, Carola J.; Labra, Valeria C.; Salgado Cortés, Nicole Andrea; Rojas Vidal, Consuelo Antonia; Oyarzun, Juan E.; Cerpa Nebott, Waldo Francisco; Quintanilla, Rodrigo A.; Orellana Roca, Juan Andrés
Inhibition of astroglial hemichannels prevents synaptic transmission decline during spreading depression
(2024) Tichauer Calderón, Juan Enrique; Lira Mendieta, Matías Sebastián; Cerpa Nebott, Waldo Francisco; Orellana Roca, Juan Andrés; Sáez Carreño, Juan Carlos; Rovegno Echavarría, David Maximiliano
Spreading depression (SD) is an intriguing phenomenon characterized by massive slow brain depolarizations that affect neurons and glial cells. This phenomenon is repetitive and produces a metabolic overload that increases secondary damage. However, the mechanisms associated with the initiation and propagation of SD are unknown. Multiple lines of evidence indicate that persistent and uncontrolled opening of hemichannels could participate in the pathogenesis and progression of several neurological disorders including acute brain injuries. Here, we explored the contribution of astroglial hemichannels composed of connexin-43 (Cx43) or pannexin-1 (Panx1) to SD evoked by high-K+ stimulation in brain slices. Results Focal high-K+ stimulation rapidly evoked a wave of SD linked to increased activity of the Cx43 and Panx1 hemichannels in the brain cortex, as measured by light transmittance and dye uptake analysis, respectively. The activation of these channels occurs mainly in astrocytes but also in neurons. More importantly, the inhibition of both the Cx43 and Panx1 hemichannels completely prevented high K+-induced SD in the brain cortex. Electrophysiological recordings also revealed that Cx43 and Panx1 hemichannels critically contribute to the SD-induced decrease in synaptic transmission in the brain cortex and hippocampus. Conclusions Targeting Cx43 and Panx1 hemichannels could serve as a new therapeutic strategy to prevent the initiation and propagation of SD in several acute brain injuries.
Is There a Role for Copper in Neurodegenerative Diseases?
(2005) Cerpa Nebott, Waldo Francisco; Inestrosa Cantín, Nibaldo
Mild Traumatic Brain Injury Induces Mitochondrial Calcium Overload and Triggers the Upregulation of NCLX in the Hippocampus
(2023) Mira, Rodrigo G.; Quintanilla, Rodrigo A.; Cerpa Nebott, Waldo Francisco
Traumatic brain injury (TBI) is brain damage due to external forces. Mild TBI (mTBI) is the most common form of TBI, and repeated mTBI is a risk factor for developing neurodegenerative diseases. Several mechanisms of neuronal damage have been described in the cortex and hippocampus, including mitochondrial dysfunction. However, up until now, there have been no studies evaluating mitochondrial calcium dynamics. Here, we evaluated mitochondrial calcium dynamics in an mTBI model in mice using isolated hippocampal mitochondria for biochemical studies. We observed that 24 h after mTBI, there is a decrease in mitochondrial membrane potential and an increase in basal matrix calcium levels. These findings are accompanied by increased mitochondrial calcium efflux and no changes in mitochondrial calcium uptake. We also observed an increase in NCLX protein levels and calcium retention capacity. Our results suggest that under mTBI, the hippocampal cells respond by incrementing NCLX levels to restore mitochondrial function.
Modulation of the NMDA Receptor Through Secreted Soluble Factors
(2014) Cerpa Nebott, Waldo Francisco; Ramos Fernández, Eva.; Inestrosa Cantín, Nibaldo

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