Browsing by Author "Lira, Matias"

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    Effect of Alcohol on Hippocampal-Dependent Plasticity and Behavior: Role of Glutamatergic Synaptic Transmission
    (Frontiers Media S.A., 2020) Mira, Rodrigo G.; Lira, Matias; Cerpa Nebott Waldo Francisco; Tapia-Rojas, Cheril; Rebolledo, Daniela; Quintanilla, Rodrigo A.
    © Copyright © 2020 Mira, Lira, Tapia-Rojas, Rebolledo, Quintanilla and Cerpa. Problematic alcohol drinking and alcohol dependence are an increasing health problem worldwide. Alcohol abuse is responsible for approximately 5% of the total deaths in the world, but addictive consumption of it has a substantial impact on neurological and memory disabilities throughout the population. One of the better-studied brain areas involved in cognitive functions is the hippocampus, which is also an essential brain region targeted by ethanol. Accumulated evidence in several rodent models has shown that ethanol treatment produces cognitive impairment in hippocampal-dependent tasks. These adverse effects may be related to the fact that ethanol impairs the cellular and synaptic plasticity mechanisms, including adverse changes in neuronal morphology, spine architecture, neuronal communication, and finally an increase in neuronal death. There is evidence that the damage that occurs in the different brain structures is varied according to the stage of development during which the subjects are exposed to ethanol, and even much earlier exposure to it would cause damage in the adult stage. Studies on the cellular and cognitive deficiencies produced by alcohol in the brain are needed in order to search for new strategies to reduce alcohol neuronal toxicity and to understand its consequences on memory and cognitive performance with emphasis on the crucial stages of development, including prenatal events to adulthood.
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    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.
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    Long-term social isolation stress exacerbates sex-specific neurodegeneration markers in a natural model of Alzheimer's disease
    (2023) Oliva, Carolina A.; Lira, Matias; Jara, Claudia; Catenaccio, Alejandra; Mariqueo, Trinidad A.; Lindsay, Carolina B.; Bozinovic, Francisco; Cavieres, Grisel; Inestrosa, Nibaldo C.; Tapia-Rojas, Cheril; Rivera, Daniela S.
    Social interactions have a significant impact on health in humans and animal models. Social isolation initiates a cascade of stress-related physiological disorders and stands as a significant risk factor for a wide spectrum of morbidity and mortality. Indeed, social isolation stress (SIS) is indicative of cognitive decline and risk to neurodegenerative conditions, including Alzheimer's disease (AD). This study aimed to evaluate the impact of chronic, long-term SIS on the propensity to develop hallmarks of AD in young degus (Octodon degus), a long-lived animal model that mimics sporadic AD naturally. We examined inflammatory factors, bioenergetic status, reactive oxygen species (ROS), oxidative stress, antioxidants, abnormal proteins, tau protein, and amyloid-beta (A beta) levels in the hippocampus of female and male degus that were socially isolated from post-natal and post-weaning until adulthood. Additionally, we explored the effect of re-socialization following chronic isolation on these protein profiles. Our results showed that SIS promotes a pro-inflammatory scenario more severe in males, a response that was partially mitigated by a period of re-socialization. In addition, ATP levels, ROS, and markers of oxidative stress are severely affected in female degus, where a period of re-socialization fails to restore them as it does in males. In females, these effects might be linked to antioxidant enzymes like catalase, which experience a decline across all SIS treatments without recovery during re-socialization. Although in males, a previous enzyme in antioxidant pathway diminishes in all treatments, catalase rebounds during re-socialization. Notably, males have less mature neurons after chronic isolation, whereas phosphorylated tau and all detectable forms of A beta increased in both sexes, persisting even post re-socialization. Collectively, these findings suggest that long-term SIS may render males more susceptible to inflammatory states, while females are predisposed to oxidative states. In both scenarios, the accumulation of tau and A beta proteins increase the individual susceptibility to early-onset neurodegenerative conditions such as AD.
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    Necroptosis inhibition counteracts neurodegeneration, memory decline, and key hallmarks of aging, promoting brain rejuvenation
    (2023) Arrazola, Macarena S.; Lira, Matias; Veliz-Valverde, Felipe; Quiroz, Gabriel; Iqbal, Somya; Eaton, Samantha L.; Lamont, Douglas J.; Huerta, Hernan; Ureta, Gonzalo; Bernales, Sebastian; Cardenas, J. Cesar; Cerpa, Waldo; Wishart, Thomas M.; Court, Felipe A.
    Age is the main risk factor for the development of neurodegenerative diseases. In the aged brain, axonal degeneration is an early pathological event, preceding neuronal dysfunction, and cognitive disabilities in humans, primates, rodents, and invertebrates. Necroptosis mediates degeneration of injured axons, but whether necroptosis triggers neurodegeneration and cognitive impairment along aging is unknown. Here, we show that the loss of the necroptotic effector Mlkl was sufficient to delay age-associated axonal degeneration and neuroinflammation, protecting against decreased synaptic transmission and memory decline in aged mice. Moreover, short-term pharmacologic inhibition of necroptosis targeting RIPK3 in aged mice, reverted structural and functional hippocampal impairment, both at the electrophysiological and behavioral level. Finally, a quantitative proteomic analysis revealed that necroptosis inhibition leads to an overall improvement of the aged hippocampal proteome, including a subclass of molecular biofunctions associated with brain rejuvenation, such as long-term potentiation and synaptic plasticity. Our results demonstrate that necroptosis contributes to age-dependent brain degeneration, disturbing hippocampal neuronal connectivity, and cognitive function. Therefore, necroptosis inhibition constitutes a potential geroprotective strategy to treat age-related disabilities associated with memory impairment and cognitive decline.
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    Serine-Arginine Protein Kinase SRPK2 Modulates the Assembly of the Active Zone Scaffolding Protein CAST1/ERC2
    (2019) Arancibia, Duxan; Lira, Matias; Cruz, Yocelin; Barrera, Daniela P.; Montenegro-Venegas, Carolina; Godoy, Juan A.; Garner, Craig C.; Inestrosa, Nibaldo C.; Gundelfinger, Eckart D.; Zamorano, Pedro; Torres, Viviana, I
    Neurons release neurotransmitters at a specialized region of the presynaptic membrane, the active zone (AZ), where a complex meshwork of proteins organizes the release apparatus. The formation of this proteinaceous cytomatrix at the AZ (CAZ) depends on precise homo- and hetero-oligomerizations of distinct CAZ proteins. The CAZ protein CAST1/ERC2 contains four coiled-coil (CC) domains that interact with other CAZ proteins, but also promote self-assembly, which is an essential step for its integration during AZ formation. The self-assembly and synaptic recruitment of the Drosophila protein Bruchpilot (BRP), a partial homolog of CAST1/ERC2, is modulated by the serine-arginine protein kinase (SRPK79D). Here, we demonstrate that overexpression of the vertebrate SRPK2 regulates the self-assembly of CAST1/ERC2 in HEK293T, SH-SY5Y and HT-22 cells and the CC1 and CC4 domains are involved in this process. Moreover, the isoform SRPK2 forms a complex with CAST1/ERC2 when co-expressed in HEK293T and SH-SY5Y cells. More importantly, SRPK2 is present in brain synaptic fractions and synapses, suggesting that this protein kinase might control the level of self-aggregation of CAST1/ERC2 in synapses, and thereby modulate presynaptic assembly.