Neuroscience
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Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative diseases that overlap clinically, genetically, and pathologically. Dysregulation of fused in sarcoma (FUS) has been hypothesized to cause ALS and FTLD in gain-of-function and/or loss-of-function manners. ⋯ Furthermore, we found that nuclear FUS, but not cytoplasmic FUS, is responsible for FUS-induced neuronal cell death. These observations suggest that the gain-of-function of FUS in the nucleus contributes to the pathogenesis of FUS-linked neurodegenerative diseases.
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Recent clinical studies suggest GABA-ergic system abnormalities as a neuropathological mechanism of schizophrenia. ⋯ This study provided evidence of a key role for the GABA system in neurodevelopment associated with the etiopathogenesis of schizophrenia and showed that the observed changes are sex-dependent. Moreover, this study is the first to present a model of schizophrenia based on prenatal LPS administration, which not only produced behavioral abnormalities but also changed the cytoarchitecture of the GABA inhibitory system.
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The effect of lacosamide (LCS), a functionalized molecule with anti-convulsant properties, on ion channels was investigated, with the aid of patch clamp technology and simulation modeling. In NSC-34 neuronal cells, LCS was found to block voltage-gated Na(+) current (INa) in a frequency- and concentration-dependent manner. With the two-step voltage protocol, a minimal change in the steady-state inactivation of INa was found in the presence of LCS. ⋯ Moreover, LCS suppressed the peak amplitude of INa in embryonic cortical neurons. In human embryonic kidney (HEK293T) cells which expressed SCN5A, LCS attenuated the peak amplitude of INa, in a concentration-dependent fashion. The unique effects of LCS on NaV currents presented here may contribute to its in vivo modulation of cellular excitability.
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Connexin43 (Cx43) as a building block of gap junction channels and hemichannels exerts important functions in astrocytes. When these cells acquire a malignant phenotype Cx43 protein but not mRNA levels are downregulated, being negligible in high-grade astrocytoma or glioblastoma multiforme, the most common and deadliest of malignant primary brain tumors in adults. Some microRNAs associated to glioma target Cx43 and could explain the lack of correlation between mRNA and protein levels of Cx43 found in some high-grade astrocytomas. ⋯ We summarize data that indicate that Cx43-Src interaction inhibits the oncogenic activity of Src and promotes a conformational change in the structure of Cx43 that allosterically modifies the binding to other important signaling proteins. As a consequence, crucial cell functions, such as proliferation or migration, could be strongly affected. We propose that the knowledge of the structural basis of the antitumorigenic effect of Cx43 on astrocytomas could help to design new therapies against this incurable disease.
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Chronic stress, the administration of glucocorticoids and the prolonged activation of glucocorticoid receptors (GRs) are reported to induce affective changes in humans and rodents that resemble a depressive state. However, data concerning the behavioral and molecular effects of the selective activation of specific GRs are limited, and the conclusions derived remain debatable. In this study, our goal was to investigate the behavioral and molecular changes following the prolonged activation of GRs in mice via exposure to the specific agonist dexamethasone (DEX). ⋯ Furthermore, our results indicate a decrease in the mRNA expression of glutamate aspartate transporter (GLAST, Slc1a3), an astroglial cell marker, in the hippocampus and prefrontal cortex. These results demonstrate that the prolonged activation of GR receptors induced a depression-like state in mice, activated stress-related genes and induced a decrease in the mRNA expression of GLAST, an astroglial marker, in the prefrontal cortex and hippocampus. Together, the results reported here challenge several hypotheses concerning the role of GRs in the development of behavioral and molecular alterations relevant to stress-related disorders, such as depression, under the same experimental conditions.