Cellscience最新文献

Dendritic spines, the postsynaptic compartments of most functional excitatory synapses in the Central Nervous System (CNS), are highly dynamic structures, having the ability to grow, change shape, or retract in response to varying levels of neuronal activity. This dynamic nature of spines allows modifications in brain circuitry and connectivity, thus participating in fundamental processes such as learning, recall, and emotional behaviors. Although many studies have characterized the precise molecular identities and signaling pathways by which spines initially form, little is known about the actual time course over which they mature into functional postsynaptic compartments of excitatory synapses. A recent publication in Neuron addresses this issue by studying dendritic spine growth in response to multiphoton glutamate uncaging, simultaneously monitoring the amplitudes of the resultant postsynaptic currents and intracellular Ca(2+) transients within individual spines in CA1 pyramidal neurons in organotypic cultures of postnatal hippocampal slices. The authors describe that dendritic spines are able to respond to glutamate shortly after their formation, leading to the conclusion that spine growth and glutamate receptor recruitment are closely coupled temporally. AMPA receptor-mediated currents exhibited similar amplitudes in newly formed spines compared with older, more mature spines when their volume was taken into account. In addition, NMDA receptor-mediated currents also appeared early after spine formation, although the amount of Ca(2+) entry through these receptors was significantly lower in newly formed spines compared to older, mature spines. Within just a couple of hours, these newly formed spines were contacted by presynaptic terminals, thus acquiring a morphological appearance indistinguishable from already existing mature excitatory synapses.

The progressive loss of effector function in the setting of chronic viral infections has been associated with the upregulation of programmed death 1 (PD-1), a negative regulator of activated T cells. In HIV infection, increased levels of PD-1 expression correlate with CD8(+) T cell exhaustion, which has been shown in vitro to be reversible with PD-1 blockade. Velu and colleagues recently reported the first in vivo study showing enhancement of a virus-specific immune response through PD-1 blockade using an anti-PD-1 antibody in an SIV-macaque model. Their results show an expansion of virus-specific, polyfunctional CD8(+) T cells. Anti-PD1 antagonists show promise as a novel immunotherapy for HIV. However, several issues including development of autoimmunity, regulatory T cells and multiple inhibitory receptors associated with CD8(+) T cell exhaustion should first be addressed to help ensure a successful response in chronic HIV infected patients.

Gap junctions can connect the cytosolic compartments of adjacent astroglia. They allow intercellular flux of low-molecular weight (< ~ 1 kDa) compounds, including metabolites and second messengers. Only recently, however, has it been proposed that gap junctions may serve an additional role in the astrocytic metabolic network which maintains synaptic transmission. The brain seems to be using a strategy analogous to power-grid systems used in modern societies to supply energy; the astrocytic 'power-grid' can deliver the metabolic energy to neurons as needed. Such an astroglial energy grid is malleable and can change the size and shape in response to metabolic activity of neuronal network to deliver energy from the root source of energy of the brain, the blood glucose, to neurons.

Amyloid-beta peptide (Abeta) oligomers are likely to underlie the earliest amnesic changes in Alzheimer's disease through impairment of synaptic function. A recent work from the laboratories of Tae-Wan Kim and Gilbert Di Paolo and colleagues implicates the phosphoinositide signaling pathway in synaptic changes due to elevation of Abeta oligomers. Given that phosphatidylinositol 4,5-bisphosphate (PIP2) is central to many essential processes in neurons including neuronal and synaptic function, reduction in the levels of PIP2 in response to oligomeric Abeta could explain many of the phenotypes that have been observed with oligomeric Abeta. The data open up a new target for protecting neurons from Abeta-induced synaptic impairment.

A small subset of retinal ganglion cells projecting to the suprachiasmatic nucleus and other brain areas, is implicated in non-image forming visual responses to environmental light such as the pupillary light reflex, seasonal adaptations in physiology, photic inhibition of nocturnal melatonin release, and modulation of sleep, alertness and activity. These cells are intrinsically photosensitive (ipRGCs) and express an opsin-like photopigment called melanopsin. Two recent studies utilizing selective genetic ablation of ipRGCs demonstrate the key role of these inner retinal cells in conveying luminance signals to the brain for non-image forming visual processing. These findings advance our understanding of functional organization of a novel photosensory system in the mammalian retina, demonstrating well-defined roles for ipRGCs in circadian timing and other homeostatic functions related to ambient illumination.

The endless quest for the 'fountain of youth' has led to the discovery of a family of molecules known as sirtuins in humans, or silent mating type information regulator 2 (Sir2) in yeast, which are associated with longevity in yeast, nematodes, drosophila and rodents. Although sirtuins have yet to be proven to delay aging and promote longevity in humans, they promise 'healthy aging', an ideal of modern society. This review emphasizes the role of various sirtuins in maintaining glucose homeostasis, the therapeutic potential of sirtuin modulators in the prevention and treatment of diabetes, and the emerging associations of SIRT genetic polymorphisms with human longevity.

Sirtuin activators, including small molecules such as polyphenols and resveratrol, are much desired due to their potential to ameliorate metabolic disorder and delay or prevent aging. In contrast, recent studies demonstrate that targeted silencing of sirtuin 1 (SIRT1) expression or activity by the deleted in breast cancer 1 (DBC1) may be beneficial by promoting p53-induced apoptosis in cancer cells, and by sensitizing cancerous cells to radiation therapy. Negative SIRT1 regulation also alleviates gene-repression associated with fragile X mental retardation syndrome. The targeted activation or inhibition of SIRT1 activity therefore emerges as a critical point of regulation in disease pathogenesis.

Astrocytes perform vital maintenance, functional enhancement, and protective roles for their associated neurons; however these same mechanisms may become deleterious for neurons under some conditions. In this review, we highlight two normally protective pathways, the endoplasmic reticulum (ER) stress response and an endogenous antioxidant response, which may become neurotoxic when activated in astrocytes during the inflammation associated with neurodegeneration. Stimulation of these multifaceted pathways affects a panoply of cellular processes. Of particular importance is the effect these pathways have on the homeostasis of the excitatory amino acid neurotransmitter, glutamate. The endogenous antioxidant response increases extracellular glutamate in the pursuit of making the cellular antioxidant, glutathione, by increasing expression of the xCT subunit of the cystine/glutamate antiporter. Meanwhile, inflammatory mediators such as TNFα reduce levels of membrane-bound glutamate scavenging proteins such as the excitatory amino acid transporters. Together, these cellular activities may result in a net increase in extracellular glutamate that could alter neuronal function and lead to excitotoxicity. Here we discuss the role of N-methyl-D-aspartate receptors, which, when excessively stimulated by glutamate, can cause neuronal dysfunction and loss via activation of calpains. While there are other pathways acting in concert or parallel to those we describe here, this review explores a rationale to explain how two protective mechanisms may result in neuronal loss during neurodegeneration.

Brain glucose-sensing mechanisms are implicated in the regulation of feeding behavior and hypoglycemic-induced hormonal counter-regulation. This commentary discusses recent findings indicating that the brain senses glucose to regulate both hepatic glucose and lipid production.

Evidence from multiple laboratories has suggested the possibility that defective membrane recruitment, triggered by mutations in conserved lipid binding domains, could be a common molecular mechanism underlying carcinogenesis. Now a recent paper by Carpten et al. in Nature has identified and analyzed one such mutation; specifically, E17K in the lipid binding pocket of the Akt plextrin homology (PH domain). This study is a tour de force that (i) pinpoints a mutation widespread in human cancers, (ii) analyzes the effect of this mutation on lipid binding domain structure, (iii) shows that the mutation enhances plasma membrane recruitment, and (iv) demonstrates that such recruitment is linked to Akt pathway superactivation, cellular transformation and tumor formation. Overall, the work provides the most convincing illustration to date that a mutation altering the membrane docking of a lipid binding domain can directly trigger cancer. Furthermore, the findings raise intriguing questions regarding the mechanism by which the highly carcinogenic E17K mutation drives enhanced recruitment of the Akt PH domain to the plasma membrane.