Neuroscience
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Astrocyte dysfunction, and in particular impaired extracellular potassium spatial buffering, has been postulated to have a potential role in seizure susceptibility and ictogenesis. Inwardly rectifying potassium (Kir) channels, and specifically KIR4.1, have a predominant role in K+ homeostasis and their involvement in neuronal excitability control have been hypothesized. To avoid the severe side effects observed in Kir4.1 cKO, we studied the effects of Kir4.1 down-regulation in cortical astrocytes by using Kir4.1 RNA interference (RNAi) technique combined with in utero electroporation (IUE) at E16 and a piggyBac transposon system. ⋯ Intriguingly, immunohistochemical analysis performed on slices studied with electrophysiology revealed a reduced number of neurons generated from radial glial cells in Kir4.1- rats. We conclude that focal down-regulation of Kir4.1 channel in cortical astrocytes by Kir4.1 RNAi technique combined with IUE is not effective in altering potassium homeostasis and seizure susceptibility. This technique revealed a possible role of Kir4.1 during corticogenesis.
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Animal studies suggest that the vestibular system autoregulates its sensitivity in response to prolonged low- or high-intensity motion in order to maintain an optimal working range. In humans, corresponding attenuations of vestibular responses after prolonged high-intensity motion exposure have been demonstrated. Here we explored whether a complementary increase in human vestibular sensitivity can be induced by motion conditioning at low-intensity, subliminal amplitudes. ⋯ Vestibular sensitivity for yaw rotations remained on average unaltered after IA conditioning indicating that sensitizing effects might be selective for the end-organ-specific vestibular pathways being stimulated during conditioning. These findings demonstrate that human vestibular sensitivity can be enhanced by subliminal sensory conditioning, similar to sensitizing effects observed in other sensory modalities. Conditioning-induced sensitization of vestibular responses may be an effective treatment for decrements in vestibular sensitivity in the elderly and patients with vestibular hypofunction.
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Choline acetyltransferase (ChAT) synthesizes the neurotransmitter acetylcholine (Ach). Exogenous supplementation with ChAT can functionally compensate for decreased Ach levels and ameliorate memory and cognitive deficits. In this paper, the treatment efficacy of recombinant ChAT (peptide transduction domain (PTD)-ChAT) and donepezil were compared in aged dementia mice, and their mechanisms were explored by performing the gene function annotation and enrichment analysis of differentially expressed genes. ⋯ Donepezil was significantly correlated with the immune inflammatory response and the insulin and IGF-1 signaling pathways. Therefore, although PTD-ChAT and donepezil were both effective in the treatment of aged dementia mice, their mechanisms were significantly different. Our research indicated that PTD-ChAT has potential promise for research on new drugs for AD treatment.
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Recent studies indicate that neuroimmune factors, including the cytokine interleukin-6 (IL-6), play a role in the CNS actions of alcohol. The cerebellum is a sensitive target of alcohol, but few studies have examined a potential role for neuroimmune factors in the actions of alcohol on this brain region. A number of studies have shown that synaptic transmission, and in particular inhibitory synaptic transmission, is an important cerebellar target of alcohol. ⋯ Multiple cerebellar synaptic proteins were assessed by Western blot. Results show that IL-6 and CIE/withdrawal have both unique and common actions that affect synaptic protein expression. These common targets could provide sites for IL-6/alcohol exposure/withdrawal interactions and play an important role in cerebellar symptoms of alcohol use such as ataxia.
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Astrocytes are major glial cells critical in assisting the function of the central nervous system (CNS), but the functional changes and regulation mechanism of reactive astrocytes are still poorly understood in CNS diseases. In this study, mouse primary astrocytes were cultured, and inflammatory insult was performed to observe functional changes in astrocytes and the involvement of Notch-PI3K-AKT signaling activation through immunofluorescence, PCR, Western blot, CCK-8, and inhibition experiments. Notch downstream signal Hes-1 was clearly observed in the astrocytes, and Notch signal inhibitor GSI dose-dependently decreased the cleaved Notch-l level without an influence on cell viability. ⋯ While an increase in MyD88, NF-кB, and phosphor-NF-кB was confirmed, upregulation of PI3K, AKT, and phosphor-AKT was observed in the activated astrocytes with LPS+IFNγ insult and was reduced by GSI treatment. Inhibitor experiments showed that inhibition of Notch-PI3K-AKT signaling activation reduced the pro-inflammatory cytokine production triggered by LPS+IFNγ inflammatory insult. This study showed that the reactive astrocytes displayed pro-inflammatory adaptability through Notch-PI3K-AKT signaling activation in response to inflammatory stimulation, suggesting that the Notch-PI3K-AKT pathway in reactive astrocytes may serve as a promising target against CNS inflammatory disorders.