分类: 生物学 >> 生物物理学 >> 神经科学 提交时间: 2016-06-06
摘要: Previous studies have shown that the Hippo pathway effector yes-associated protein (YAP) plays an important role in maintaining stem cell proliferation. However, the precise molecular mechanism of YAP in regulating murine embryonic neural stem cells (NSCs) remains largely unknown. Here, we show that bone morphogenetic protein-2 (BMP2) treatment inhibited the proliferation of mouse embryonic NSCs, that YAP was critical for mouse NSC proliferation, and that BMP2 treatment-induced inhibition of mouse NSC proliferation was abrogated by YAP knockdown, indicating that the YAP protein mediates the inhibitory effect of BMP2 signaling. Additionally, we found that BMP2 treatment reduced YAP nuclear translocation, YAP-TEAD interaction, and YAP-mediated transactivation. BMP2 treatment inhibited YAP/TEAD-mediated Cyclin D1 (ccnd1) expression, and knockdown of ccnd1 abrogated the BMP2-mediated inhibition of mouse NSC proliferation. Mechanistically, we found that Smad1/4, effectors of BMP2 signaling, competed with YAP for the interaction with TAED1 and inhibited YAP's cotranscriptional activity. Our data reveal mechanistic cross talk between BMP2 signaling and the Hippo-YAP pathway in murine NSC proliferation, which may be exploited as a therapeutic target in neurodegenerative diseases and aging.
分类: 生物学 >> 生物物理学 >> 神经科学 提交时间: 2016-05-11
摘要: Main ProblemEpilepsy is one of the more common neurological disorders. The medication is often ineffective to the patients suffering from intractable temporal lobe epilepsy (TLE). As their seizures are usually self-terminated, the elucidation of the mechanism underlying endogenous seizure termination will help to find a new strategy for epilepsy treatment. We aim to examine the role of inhibitory interneurons in endogenous seizure termination in TLE patients. MethodsWhole-cell recordings were conducted on inhibitory interneurons in seizure-onset cortices of intractable TLE patients and the temporal lobe cortices of nonseizure individuals. The intrinsic property of the inhibitory interneurons and the strength of their GABAergic synaptic outputs were measured. The quantitative data were introduced into the computer-simulated neuronal networks to figure out a role of these inhibitory units in the seizure termination. ResultsIn addition to functional downregulation, a portion of inhibitory interneurons in seizure-onset cortices were upregulated in encoding the spikes and controlling their postsynaptic neurons. A patch-like upregulation of inhibitory neurons in the local network facilitated seizure termination. The upregulations of both inhibitory neurons and their output synapses synergistically shortened seizure duration, attenuated seizure strength, and terminated seizure propagation. ConclusionAutomatic seizure termination is likely due to the fact that a portion of the inhibitory neurons and synapses are upregulated in the seizure-onset cortices. This mechanism may create novel therapeutic strategies to treat intractable epilepsy, such as the simultaneous upregulation of cortical inhibitory neurons and their output synapses.
分类: 生物学 >> 生物物理学 >> 细胞生物学 提交时间: 2016-05-11
摘要: In Alzheimer's disease (AD), activated microglia invade and surround beta-amyloid plaques, possibly contributing to the aggregation of amyloid beta (A beta), which affect the survival of neurons and lead to memory loss. Phosphodiesterase-5 (PDE-5) inhibitors have recently been shown a potential therapeutic effect on AD. In this study, the effects of yonkenafil (yonk), a novel PDE-5 inhibitor, on cognitive behaviors as well as the pathological features in transgenic AD mice were investigated. Seven-month-old APP/PSI transgenic mice were treated with yonk (2, 6, or 18 mg/kg, intraperitoneal injection (i.p.)) or sildenafil (slid) (6 mg/kg, i.p.) daily for 3 months and then behavioral tests were performed. The results demonstrated that yonk improved nesting-building ability, ameliorated working memory deficits in the Y-maze tasks, and significantly improved learning and memory function in the Morris water maze (MWM) tasks. In addition, yonk reduced the area of A beta plaques, and inhibited over-activation of microglia and astrocytes. Furthermore, yonk increased neurogenesis in the dentate granule brain region of APP/PSI mice, indicated by increased BrdU(+)/NeuN(+) and BrdU(+)/DCX+ cells compared to vehicle-treated transgenic mice. These results suggest that yonk could rescue cognitive deficits by ameliorated amyloid burden through regulating APP processing, inhibited the over-activation of microglia and astrocytes as well as restored neurogenesis. (C) 2015 Elsevier Ireland Ltd. All rights reserved.