Synaptic Plasma Membrane Tubulin May Be an Integral Constituent

Abstract: Mild detergent extraction of chick brain synaptic plasma membranes followed by gel electrophoresis suggests that synaptic plasma membrane tubulin is an integral component. Although some of the synaptic plasma membrane tubulin might be aggregates, that possibility is not supported by the observation that tubulin aggregates that are added to synaptosomes before synaptic subfractionation do not partition with synaptic plasma membranes during membrane isolation.     

Apparent Inhibition of beta-Fructosidase Secretion by Tunicamycin May Be Explained by Breakdown of the Unglycosylated Protein during Secretion

Suspension-cultured carrot (Daucus carota) cells synthesize and secrete β-fructosidase, a glycoprotein with asparagine-linked glycans. Treatment of the cells with tunicamycin completely inhibits the apparent secretion of β-fructosidase as measured by the accumulation of the radioactive protein in the cell wall or the culture medium. In the past, such a result has been interpreted as an inhibition of secretion by tunicamycin, but we suggest another explanation based on the following results. In the presence of tunicamycin, unglycosylated β-fructosidase is synthesized and is associated with an endoplasmic-reticulum-rich microsomal fraction. Pulse-chase experiments show that the unglycosylated β-fructosidase does not remain in the cells and appears to be secreted in the same way as glycosylated β-fructosidase; however, no radioactive, unglycosylated β-fructosidase accumulates extracellularly (cell wall or medium). Protoplasts obtained from carrot cells secrete β-fructosidase protein and activity, and treatment of the protoplasts with tunicamycin results in the synthesis of unglycosylated β-fructosidase. In the presence of tunicamycin, there is no accumulation of β-fructosidase activity or unglycosylated β-fructosidase polypeptide in the protoplast incubation medium. These results are consistent with the interpretation that the glycans of β-fructosidase are necessary for its stability, and that in these suspension-cultured cells, the unglycosylated enzyme is degraded during the last stage(s) of secretion, or immediately after its arrival in the wall.     

When Natural Behavior Engages Working Memory

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Association by Synaptic Facilitation in Highly Damped Neural Nets

Cognitive functions are sought in a homogeneous, randomly connected net of neuron-like elements. Information is assumed to be contained in the instantaneous states of the system, which specify the firing states (off or on) of each neuron in the net. The hypothesis of synaptic facilitation is assumed to be the basis of learning and memory. Owing to the high degree of damping no reverberations occur in the net. However, close analogies can be found between the performance of the net and known association functions of the cerebral cortex, among them various types of conditioned reflexes. The data are obtained by a combination of mathematical analysis and computer simulation. It is emphasized that the biological entity simulated by this model is at best a limited component of the cerebral cortex.     

Quantifying the Reconfiguration of Intrinsic Networks during Working Memory

Rapid, flexible reconfiguration of connections across brain regions is thought to underlie successful cognitive control. Two intrinsic networks in particular, the cingulo-opercular (CO) and fronto-parietal (FP), are thought to underlie two operations critical for cognitive control: task-set maintenance/tonic alertness and adaptive, trial-by-trial updating. Using functional magnetic resonance imaging, we directly tested whether the functional connectivity of the CO and FP networks was related to cognitive demands and behavior. We focused on working memory because of evidence that during working memory tasks the entire brain becomes more integrated. When specifically probing the CO and FP cognitive control networks, we found that individual regions of both intrinsic networks were active during working memory and, as expected, integration across the two networks increased during task blocks that required cognitive control. Crucially, increased integration between each of the cognitive control networks and a task-related, non-cognitive control network (the hand somatosensory-motor network; SM) was related to increased accuracy. This implies that dynamic reconfiguration of the CO and FP networks so as to increase their inter-network communication underlies successful working memory.     

Enhanced Botrytis cinerea Resistance of Arabidopsis Plants Grown in Compost May Be Explained by Increased Expression of Defense-Related Genes,as Revealed by Microarray Analysis

Composts are the products obtained after the aerobic degradation of different types of organic matter waste and can be used as substrates or substrate/soil amendments for plant cultivation. There is a small but increasing number of reports that suggest that foliar diseases may be reduced when using compost, rather than standard substrates, as growing medium. The purpose of this study was to examine the gene expression alteration produced by the compost to gain knowledge of the mechanisms involved in compost-induced systemic resistance. A compost from olive marc and olive tree leaves was able to induce resistance against Botrytis cinerea in Arabidopsis, unlike the standard substrate, perlite. Microarray analyses revealed that 178 genes were differently expressed, with a fold change cut-off of 1, of which 155 were up-regulated and 23 were down-regulated in compost-grown, as against perlite-grown plants. A functional enrichment study of up-regulated genes revealed that 38 Gene Ontology terms were significantly enriched. Response to stress, biotic stimulus, other organism, bacterium, fungus, chemical and abiotic stimulus, SA and ABA stimulus, oxidative stress, water, temperature and cold were significantly enriched, as were immune and defense responses, systemic acquired resistance, secondary metabolic process and oxireductase activity. Interestingly, PR1 expression, which was equally enhanced by growing the plants in compost and by B. cinerea inoculation, was further boosted in compost-grown pathogen-inoculated plants. Compost triggered a plant response that shares similarities with both systemic acquired resistance and ABA-dependent/independent abiotic stress responses.     

Synaptotoxicity of Alzheimer Beta Amyloid Can Be Explained by Its Membrane Perforating Property

The mechanisms that induce Alzheimer''s disease (AD) are largely unknown thereby deterring the development of disease-modifying therapies. One working hypothesis of AD is that Aβ excess disrupts membranes causing pore formation leading to alterations in ionic homeostasis. However, it is largely unknown if this also occurs in native brain neuronal membranes. Here we show that similar to other pore forming toxins, Aβ induces perforation of neuronal membranes causing an increase in membrane conductance, intracellular calcium and ethidium bromide influx. These data reveal that the target of Aβ is not another membrane protein, but that Aβ itself is the cellular target thereby explaining the failure of current therapies to interfere with the course of AD. We propose that this novel effect of Aβ could be useful for the discovery of anti AD drugs capable of blocking these “Aβ perforates”. In addition, we demonstrate that peptides that block Aβ neurotoxicity also slow or prevent the membrane-perforating action of Aβ.     

Tissue‐Specificity and Ethnic Diversity in Obesity‐Related Risk of Cancer May Be Explained by Variability in Insulin Response and Insulin Signaling Pathways

Obesity is a predisposing risk factor for several chronic diseases. The link between obesity and cancer appears to be particularly complex. Notably only the risk for development of specific cancers appear to be affected. Moreover, the obesity‐related risk of cancer is very different across ethnic groups. African‐Americans appear particularly prone, whereas Hispanics appear to be relatively protected. Obesity is associated with increased levels of circulating insulin. These levels of elevated insulin may serve to promote proliferation of fat cells to accommodate the elevated nutrient flux. However, elevated levels of insulin may be a major mediating factor influencing cancer risk. This hypothesis alone cannot explain the complexity of the phenomenon. We suggest here that the different insulin responses to obesity of different ethnic groups may explain their different risk profiles. Moreover, we speculate that tissue‐specific variations in the insulin signaling pathways may underlie their differential susceptibility to tumorigenesis in the face of elevated obesity. Elevated cancer risk may be an unwanted side effect of insulin responding to elevated nutrient flux in the obese which it serves to proliferate fat cells that provide a location for storage of ingested fat, which consequently prevents ectopic fat storage. Hence, while Hispanics may be protected from cancer risk in obesity because of their lower insulin response, they have an elevated risk of fatty liver disease. Reduction of insulin levels in obesity as a strategy to reduce cancer risk may pose additional problems unless it is combined also with interventions that aim to limit nutrient influx.     

Stromalin Constrains Memory Acquisition by Developmentally Limiting Synaptic Vesicle Pool Size

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Reconstructions of Information in Visual Spatial Working Memory Degrade with Memory Load

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Emergence of Functional Specificity in Balanced Networks with Synaptic Plasticity

In rodent visual cortex, synaptic connections between orientation-selective neurons are unspecific at the time of eye opening, and become to some degree functionally specific only later during development. An explanation for this two-stage process was proposed in terms of Hebbian plasticity based on visual experience that would eventually enhance connections between neurons with similar response features. For this to work, however, two conditions must be satisfied: First, orientation selective neuronal responses must exist before specific recurrent synaptic connections can be established. Second, Hebbian learning must be compatible with the recurrent network dynamics contributing to orientation selectivity, and the resulting specific connectivity must remain stable for unspecific background activity. Previous studies have mainly focused on very simple models, where the receptive fields of neurons were essentially determined by feedforward mechanisms, and where the recurrent network was small, lacking the complex recurrent dynamics of large-scale networks of excitatory and inhibitory neurons. Here we studied the emergence of functionally specific connectivity in large-scale recurrent networks with synaptic plasticity. Our results show that balanced random networks, which already exhibit highly selective responses at eye opening, can develop feature-specific connectivity if appropriate rules of synaptic plasticity are invoked within and between excitatory and inhibitory populations. If these conditions are met, the initial orientation selectivity guides the process of Hebbian learning and, as a result, functionally specific and a surplus of bidirectional connections emerge. Our results thus demonstrate the cooperation of synaptic plasticity and recurrent dynamics in large-scale functional networks with realistic receptive fields, highlight the role of inhibition as a critical element in this process, and paves the road for further computational studies of sensory processing in neocortical network models equipped with synaptic plasticity.     

Survival of Male Patients with Incontinentia Pigmenti Carrying a Lethal Mutation Can Be Explained by Somatic Mosaicism or Klinefelter Syndrome

Incontinentia pigmenti (IP), or "Bloch-Sulzberger syndrome," is an X-linked dominant disorder characterized by abnormalities of skin, teeth, hair, and eyes; skewed X-inactivation; and recurrent miscarriages of male fetuses. IP results from mutations in the gene for NF-kappaB essential modulator (NEMO), with deletion of exons 4-10 of NEMO accounting for >80% of new mutations. Male fetuses inheriting this mutation and other "null" mutations of NEMO usually die in utero. Less deleterious mutations can result in survival of males subjects, but with ectodermal dysplasia and immunodeficiency. Male patients with skin, dental, and ocular abnormalities typical of those seen in female patients with IP (without immunodeficiency) are rare. We investigated four male patients with clinical hallmarks of IP. All four were found to carry the deletion normally associated with male lethality in utero. Survival in one patient is explained by a 47,XXY karyotype and skewed X inactivation. Three other patients possess a normal 46,XY karyotype. We demonstrate that these patients have both wild-type and deleted copies of the NEMO gene and are therefore mosaic for the common mutation. Therefore, the repeat-mediated rearrangement leading to the common deletion does not require meiotic division. Hypomorphic alleles, a 47,XXY karyotype, and somatic mosaicism therefore represent three mechanisms for survival of males carrying a NEMO mutation.     

Novel Bursting Patterns Emerging from Model Inhibitory Networks with Synaptic Depression

Studies show that short-term synaptic plasticity plays important roles in neural coding and the normal operation of the synapse. Basket cells in the hippocampus demonstrate this plasticity in the form of synaptic depression, and recent in vivo work indicates that basket cell activities contribute significantly to hippocampal output associated with different behavioural states. Thus it is essential to understand the generation and synchronization of patterns produced by basket cell networks with depression. We study two-cell model inhibitory networks with depression and obtain alternating bursting patterns and synchronous activity occurring between bursts. We describe mechanisms for how these patterns emerge by performing several simulations in the plane of different depression time constants, tauD. Such patterns might contribute significantly to various population activities observed in the hippocampus.     

Memory Capacity of Networks with Stochastic Binary Synapses

In standard attractor neural network models, specific patterns of activity are stored in the synaptic matrix, so that they become fixed point attractors of the network dynamics. The storage capacity of such networks has been quantified in two ways: the maximal number of patterns that can be stored, and the stored information measured in bits per synapse. In this paper, we compute both quantities in fully connected networks of N binary neurons with binary synapses, storing patterns with coding level , in the large and sparse coding limits (). We also derive finite-size corrections that accurately reproduce the results of simulations in networks of tens of thousands of neurons. These methods are applied to three different scenarios: (1) the classic Willshaw model, (2) networks with stochastic learning in which patterns are shown only once (one shot learning), (3) networks with stochastic learning in which patterns are shown multiple times. The storage capacities are optimized over network parameters, which allows us to compare the performance of the different models. We show that finite-size effects strongly reduce the capacity, even for networks of realistic sizes. We discuss the implications of these results for memory storage in the hippocampus and cerebral cortex.     

Structural Damage Induced by Peroxidation May Account for Functional Impairment of Heavy Synaptic Mitochondria

Coenzyme Q distribution, as well as respiratory chain features, in rat brain mitochondria depend on mitochondrial subpopulation, brain region and age. Heavy mitochondria (HM) usually display the lowest content of respiratory components and the lowest enzymatic activities and it has been suggested that they represent the oldest mitochondrial population. In this study, we confirmed that HM are considerably compromised in their structure. In fact, HM showed to have the highest hydroperoxide content and the most consistent modifications in their fatty acid pattern with wide loss of fatty acids (or part of them) in the phospholipid moiety. Such situation could explain the typical impairment of HM and could support the hypothesis that they represent an old mitochondrial population.     

Stress-Induced Translational Control in Potato Tubers May Be Mediated by Polysome-Associated Proteins

Potato tubers exhibit distinct responses to wounding and hypoxia that include selective translation of stress-induced mRNAs. Newly synthesized wound-response mRNAs are bound to polysomes, whereas preexisting mRNAs are displaced and degraded. mRNAs that are induced and translated during hypoxic conditions are bound to ribosomes as expected. However, preexisting wound-response mRNAs whose translation is inhibited during hypoxia remain bound to polysomes, indicating that there are at least two distinct mechanisms by which translation is regulated in response to stress conditions. A 32-kD phosphoprotein is associated with polyribosomes from wounded tubers. This protein remains polysome bound as long as wound-response mRNAs are present, even during hypoxia when these mRNAs are no longer translated. However, association of the 32-kD protein with polysomes is not elicited by hypoxic stress alone. The kinase that phosphorylates this protein is active only for the first 24 hr after wounding and is not active during periods of hypoxia. This protein may mediate recognition of the wound-response mRNAs by ribosomes.