Neuroscience
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Neuropathy target esterase (NTE) is a protein involved in the development of a polyneuropathy caused by exposure to certain organophosphorus compounds. In vivo and in vitro studies have also associated NTE with embryonic development since NTE null mice embryos are non-viable, and silencing the NTE-codifying gene (Pnpla6) in mouse embryonic stem cells strongly alters the differentiation of vascular and nervous systems. In this paper, human embryonal carcinoma stem cells human-derived NTera2/D1 (hNT2) are used as an in vitro neurodifferentiation model to determine whether PNPLA6 silencing is able to alter the differentiation process. ⋯ Microarray data analysis of the PNPLA6-silenced cells showed alterations in several developmental processes, mainly neurogenesis and epithelium tube morphogenesis. PNPLA6 silencing also led to a reduction in electrical activity and an altered neuronal phenotype. This work is the first proof supporting the hypothesis that NTE plays a role in human early neurodevelopment using a human cell differentiation model.
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The C-terminal fragments-25(CTF25) of TDP-43 is a fragment of TAR DNA-binding protein 43kDa (TDP-43), which is involved in RNA metabolism, neurite outgrowth, and neuronal development and stress granules. Not until recently did evidence suggest that CTF25 might play an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. However, mechanical details on CTF25 causing motor neuron degeneration still remain unknown. ⋯ Furthermore, the neurotoxicity of CTF25 of TDP-43 was dependent on proteasome activity. In addition, electron microscopy showed mitochondrial swelling and cristae dilation in cells expressing CTF25 and that CTF25 aggregates were characterized by filamentous bundles and electron dense granular material. In conclusion, the new cellular model mimics classical toxic TDP-43 cellular model and interestingly the toxicity of CTF25 is dependent on the proteasome.
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Empathy for pain, a widely studied sub-form of empathy, is an ability to recognize and share the pain of others. It involves brain regions associated with the emotional component of pain. Recent studies found that emotional pain could be modulated by stimulating the dorsolateral prefrontal cortex (DLPFC) with transcranial direct current stimulation (tDCS). ⋯ It was found that ratings for others' pain increased in subjects with an anodal tDCS of the DLPFC in comparison to those with sham tDCS, indicating enhanced pain empathy with the anodal tDCS. Furthermore, the changes of ratings for others' pain were positively correlated with the changes of pain-related self-unpleasantness. These findings indicate that tDCS could modulate pain empathy and be used as a potential tool for modulating diseases accompanied with empathy deficits.
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Caffeine, a methylated derivative of xanthine and widely consumed psychoactive substance, acts in several targets in the nervous system. We investigated its role in retinal explants of chick embryo analyzing the role of purinergic receptors in [(3)H]-GABA release induced by d-aspartate (d-asp). d-Asp increases GABA-release 4.5-fold when compared to basal levels from 13-day-old chick embryo retinal explants. Caffeine 500μM elevated d-asp-induced GABA release in 60%. ⋯ The GluN2B subunit-containing NMDAR antagonist ifenprodil inhibited the caffeine effect. Our results suggest that caffeine potentiates d-asp-induced GABA release, which is mediated by GAT-1, via inhibition of adenosine A1 receptor and activation of the PKA pathway. Regulation of NMDAR by phosphorylation of GluN2B subunit by a SFK may also be involved in the effect promoted by caffeine.
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Nitric oxide (NO) and oxidative stress caused by reactive oxygen species (ROS) accumulation are two important factors that lead to the progression of human neurological diseases. NO can be detrimental or protective to neurons under oxidative toxicity; however, in the case of brain exposure to oxidative stress, in addition to neurons, the existence of glia may also be disturbed by toxic ROS. The influence NO will have on ROS-mediated glial injury remains unclear. ⋯ H2O2 at toxic levels activated p38 mitogen-activated protein kinases (MAPK) and p53 pathways and increased DNA double strand breaks (DSBs) in microglia, whereas the rescue exerted by sublytic SNAP against toxic H2O2 occurred via the activation of both Akt and extracellular-signal-regulated kinase (ERK) cascades and decreased DNA DSBs. Moreover, a sublytic concentration of SNAP induced both heat shock protein 70 and heme oxygenase-1, which may be involved in decreasing the susceptibility of microglia to H2O2 toxicity. These results suggest that NO exhibits a concentration-dependent dual action of weakening or enhancing oxidative injury in mixed glia, particularly microglia.