From periodic travelling waves to travelling fronts in the spike-diffuse-spike model of dendritic waves

In the vertebrate brain excitatory synaptic contacts typically occur on the tiny evaginations of neuron dendritic surface known as dendritic spines. There is clear evidence that spine heads are endowed with voltage-dependent excitable channels and that action potentials invade spines. Computational models are being increasingly used to gain insight into the functional significance of a spine with an excitable membrane. The spike-diffuse-spike (SDS) model is one such model that admits to a relatively straightforward mathematical analysis. In this paper we demonstrate that not only can the SDS model support solitary travelling pulses, already observed numerically in more detailed biophysical models, but that it has periodic travelling wave solutions. The exact mathematical treatment of periodic travelling waves in the SDS model is used, within a kinematic framework, to predict the existence of connections between two periodic spike trains of different interspike interval. The associated wave front in the sequence of interspike intervals travels with a constant velocity without degradation of shape, and might therefore be used for the robust encoding of information.     

Calcium dynamics in dendritic spines: a link to structural plasticity

Calcium signals evoked either by action potential or by synaptic activity play a crucial role for the synaptic plasticity within an individual spine. Because of the small size of spine and the indicators commonly used to measure spine calcium activity, calcium function can be severely disrupted. Therefore, it is very difficult to explain the exact relationship between spine geometry and spine calcium dynamics. Recently, it has been suggested that the medium range of calcium which induces long term potentiation leads to the structural stability stage of spines, while very low or very high amount of calcium leads to the long term depression stage which results in shortening and eventually pruning of spines. Here we propose a physiologically realistic computational model to examine the role of calcium and the mechanisms that govern its regulation in the spine morphology. Calcium enters into spine head through NMDA and AMPA channels and is regulated by internal stores. Contribution of this calcium in the induction of long term potentiation and long term depression is also discussed. Further it has also been predicted that the presence of internal stores depletes the total calcium accumulation in cytosol which is in agreement with the recent experimental and theoretical studies.     

Distribution of MAP 2 in dendritic spines and its colocalization with actin

Summary The distribution of MAP2 and actin in dendritic spines of the visual and cerebellar cortices, dentate fascia, and hippocampus was determined by using immunogold electron microscopy. By this approach, we have confirmed the presence of MAP2 in dendritic spines and identified substructures within the spine compartment showing MAP2 immunoreactivity. MAP2 immunolabeling was mainly associated with filaments which reacted with a monoclonal anti-actin antibody. Also, by immunogold double-labeling we colocalized MAP2 with actin on the endomembranes of the spine apparatus, smooth endoplasmic reticulum, and in the postsynaptic density. Labeling was nearly absent in axons and axonal terminals. These results indicate that MAP2 is an actin-associated protein in dendritic spines. Thus, MAP2 may organize actin filaments in the spine and endow the actin network of the spine with dynamic properties that are necessary for synaptic plasticity.     

Many faces of drebrin: from building dendritic spines and stabilizing gap junctions to shaping neurite-like cell processes

In this review we consider the multiple functions of developmentally regulated brain protein (drebrin), an actin-binding protein, in the formation of cellular polarity in different cell types. Drebrin has a well-established role in the morphogenesis, patterning and maintenance of dendritic spines in neurons. We have recently shown that drebrin also stabilizes Connexin-43 containing gap junctions at the plasma membrane. The latest literature and our own data suggest that drebrin may be broadly involved in shaping cell processes and in the formation of stabilized plasma membrane domains, an effect that is likely to be of crucial significance for formation of cell polarity in both neuronal and non-neuronal types. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Targeting of proteins of the striatin family to dendritic spines: role of the coiled-coil domain

Striatin, SG2NA and zinedin, the three mammalian members of the striatin family are multimodular WD-repeat, calmodulin and calveolin-binding proteins. These scaffolding proteins, involved in both signaling and trafficking, are highly expressed in neurons. Using ultrastructural immunolabeling, we showed that, in Purkinje cells and hippocampal neurons, SG2NA is confined to the somatodendritic compartment with the highest density in dendritic spines. In cultured hippocampal neurons, SG2NA is also highly concentrated in dendritic spines. By expressing truncated forms of HA-tagged SG2NAbeta, we demonstrated that the coiled-coil domain plays an essential role in the targeting of SG2NA within spines. Furthermore, co-immunoprecipitation experiments indicate that this coiled-coil domain is also crucial for the homo- and hetero-oligomerization of these proteins. Thus, oligomerization of the striatin family proteins is probably an obligatory step for their routing to the dendritic spines, and hetero-oligomerization explains why all these proteins are often co-expressed in the neurons of the rat brain and spinal cord.     

Radiolarian skeleton: Morphology of spines,internal framework,and primary sphere

The morphology and evolution of the internal framework, primary inner sphere, and various spines of radiolarian skeletons are considered. A new scheme of successive stages of spine formation is offered. The convergent similarity of radiolarian spines and sponge spicules are discussed.     

Analysis of an excitable dendritic spine with an activity-dependent stem conductance

 Dendritic spines are the major target for excitatory synaptic inputs in the vertebrate brain. They are tiny evaginations of the dendritic surface consisting of a bulbous head and a tenuous stem. Spines are considered to be an important locus for plastic changes underlying memory and learning processes. The findings that synaptic morphology may be activity-dependent and that spine head membrane may be endowed with voltage-dependent (excitable) channels is the motivation for this study. We first explore the dynamics, when an excitable, yet morphologically fixed spine receives a constant current input. Two parameter Andronov–Hopf bifurcation diagrams are constructed showing stability boundaries between oscillations and steady-states. We show how these boundaries can change as a function of both the spine stem conductance and the conductance load of the attached dendrite. Building on this reference case an idealized model for an activity-dependent spine is formulated and analyzed. Specifically we examine the possibility that the spine stem resistance, the tunable “synaptic weight” parameter identified by Rall and Rinzel, is activity-dependent. In the model the spine stem conductance depends (slowly) on the local electrical interactions between the spine head and the dendritic cable; parameter regimes are found for bursting, steady states, continuous spiking, and more complex oscillatory behavior. We find that conductance load of the dendrite strongly influences the burst pattern as well as other dynamics. When the spine head membrane potential exhibits relaxation oscillations a simple model is formulated that captures the dynamical features of the full model. Received: 10 January 1997/Revised version: 25 March 1997     

Structural dynamics of dendritic spines: Molecular composition,geometry and functional regulation

The development of dendritic spines with specific geometry and membrane composition is critical for proper synaptic function. Specific spine membrane architecture, sub-spine microdomains and spine head and neck geometry allow for well-coordinated and compartmentalized signaling, disruption of which could lead to various neurological diseases. Research from neuronal cell culture, brain slices and direct in vivo imaging indicates that dendritic spine development is a dynamic process which includes transition from small dendritic filopodia through a series of structural refinements to elaborate spines of various morphologies. Despite intensive research, the precise coordination of this morphological transition, the changes in molecular composition, and the relation of spines of various morphologies to function remain a central enigma in the development of functional neuronal circuits. Here, we review research so far and aim to provide insight into the key events that drive structural change during transition from immature filopodia to fully functional spines and the relevance of spine geometry to function.     

Assessment of estradiol influence on spatial tasks and hippocampal CA1 spines: evidence that the duration of hormone deprivation after ovariectomy compromises 17beta-estradiol effectiveness in altering CA1 spines

Two pulses of 17β-estradiol (10 µg) are commonly used to increase hippocampal CA1 apical dendritic spine density and alter spatial performance in ovariectomized (OVX) female rats, but rarely are the measures combined. The goal of this study was to use this two-pulse injection protocol repeatedly with intervening wash-out periods in the same rats to: 1) measure spatial ability using different tasks that require hippocampal function and 2) determine whether ovarian hormone depletion for an extended 10-week period reduces 17β-estradiol's effectiveness in elevating CA1 apical dendritic spine density. Results showed that two injections of 10 µg 17β-estradiol (72 and 48 h prior to testing and timed to maximize CA1 apical spine density at behavioral assessment) corresponded to improved spatial memory performance on object placement. In contrast, two injections of 5 µg 17β-estradiol facilitated spatial learning on the water maze compared to rats given two injections of 10 µg 17β-estradiol or the sesame oil vehicle. Neither 17β-estradiol dose altered Y-maze performance. As expected, the intermittent two-pulse injection protocol increased CA1 apical spine density, but 10 weeks of OVX without estradiol treatment decreased the effectiveness of 10 µg 17β-estradiol to increase CA1 apical spine density. Moreover, two pulses of 5 µg 17β-estradiol injected intermittently failed to alter CA1 apical spine density and decreased basal spine density. These results demonstrate that extended time without ovarian hormones reduces 17β-estradiol's effectiveness to increase CA1 apical spine density. Collectively, these findings highlight the complex interactions among estradiol, CA1 spine density/morphology, and task requirements, all of which contribute to behavioral outcomes.     

Rapid WAVE dynamics in dendritic spines of cultured hippocampal neurons is mediated by actin polymerization

The Wiskott-Aldrich syndrome protein family Verprolin-homologous protein (WAVE) complex has been proposed to link Rho GTPase activity with actin polymerization but its role in neuronal plasticity has never been documented. We now examined the presence, distribution and dynamics of WAVE3 in cultured hippocampal neurons. WAVE3 was localized to dendritic spines via its N-terminal domain. Green fluorescent protein (GFP)-tagged WAVE3 clusters demonstrate an F-actin-dependent high rate of local motility. Constitutive Rac activation translocates WAVE3 (via the N-terminus), to the leading edge of lamellipodia. Also, spinogenesis is associated with actin-based motility of the WAVE3 protein. Brain specific WAVE1 showed similar localization and effects on spine density. Cytoplasmic fragile X mental retardation protein interacting protein (CYFIP) and non-catalytic region of tyrosine kinase adaptor protein 1 (NCK-1), proteins that are assumed to complex with WAVE, have a somewhat similar cellular distribution and motility. We propose that the WAVE complex is a downstream effector of the Rac signaling cascade, localized to sites of novel synaptic contacts by means of its N-terminal domain, to guide local actin polymerization needed for morphological plasticity of neurons.     

A modeling framework for the study of protein glycosylation

The key step in the asparagine-linked glycosylation of secretory proteins is the transfer of oligosaccharide from a dolichol precursor to the polypeptide at an Asp-X-Ser/Thr (NXS/T) consensus sequence. It is often the case, both in cultured cells and in vivo, that this reaction does not occur for every molecule of a given protein. Thus, the cell may create two protein populations, one bearing and one lacking oligosaccharide, for each potential glycosylation site. We present a structured kinetic modeling framework of the initial glycosylation event based on a balance of available glycosylation sites through the region of endoplasmic reticulum lumen proximal to the membrane. Oligosaccharyltransferase, a multimeric protein complex, catalyzes the sugar transfer. This enzyme is integral to the endoplasmic reticulum membrane, and it is thought to act cotranslationally. The nascent polypeptide may also fold in such a way as to prevent glycosylation from occurring. The net result is a potentially complex spatial and temporal relationship among translation, glycosylation, and other cotranslational events. Model results predict how fractional glycosylation site occupancy may depend on protein synthesis rate, oligosaccharyldolichol availability, and mRNA elongation rate. Although we are currently unable to quantitatively compare predicted to experimentally obtained fractional site occupancy, we are able to determine qualitative trends which may be confirmed experimentally. (c) 1996 John Wiley & Sons, Inc.     

Democratization in a passive dendritic tree: an analytical investigation

One way to achieve amplification of distal synaptic inputs on a dendritic tree is to scale the amplitude and/or duration of the synaptic conductance with its distance from the soma. This is an example of what is often referred to as "dendritic democracy". Although well studied experimentally, to date this phenomenon has not been thoroughly explored from a mathematical perspective. In this paper we adopt a passive model of a dendritic tree with distributed excitatory synaptic conductances and analyze a number of key measures of democracy. In particular, via moment methods we derive laws for the transport, from synapse to soma, of strength, characteristic time, and dispersion. These laws lead immediately to synaptic scalings that overcome attenuation with distance. We follow this with a Neumann approximation of Green's representation that readily produces the synaptic scaling that democratizes the peak somatic voltage response. Results are obtained for both idealized geometries and for the more realistic geometry of a rat CA1 pyramidal cell. For each measure of democratization we produce and contrast the synaptic scaling associated with treating the synapse as either a conductance change or a current injection. We find that our respective scalings agree up to a critical distance from the soma and we reveal how this critical distance decreases with decreasing branch radius.     

Quantitative analysis of dendritic morphology of the alpha and delta retinal ganglion cells in the rat: A cell classification study

Type I retinal ganglion cells in the rat have been classified into several groups based on the cell body size and dendritic morphology. Considerable overlap and heterogeneity within groups have been reported, which is especially obvious for the morphology of the dendritic tree. For that purpose, we analysed quantitatively the dendritic morphology of the alpha and delta rat retinal ganglion cells, using parameters which provide information on the dendritic field size, shape of the dendritic tree and dendritic branching complexity. We show that the alpha and delta cells have significantly different dendritic field sizes. Taking into account the level of stratification of the dendritic tree, we found a difference in the properties of the dendritic morphology between alpha inner and alpha outer cells, while the opposite result was obtained for the delta inner and delta outer delta cells. In this study we also call attention to the relationship between morphological parameters and retinal eccentricity. The significance of our quantitative results in terms of present alpha and delta rat retinal ganglion cell classification is discussed.     

How predation shaped fish: the impact of fin spines on body form evolution across teleosts

It is well known that predators can induce morphological changes in some fish: individuals exposed to predation cues increase body depth and the length of spines. We hypothesize that these structures may evolve synergistically, as together, these traits will further enlarge the body dimensions of the fish that gape-limited predators must overcome. We therefore expect that the orientation of the spines will predict which body dimension increases in the presence of predators. Using phylogenetic comparative methods, we tested this prediction on the macroevolutionary scale across 347 teleost families, which display considerable variation in fin spines, body depth and width. Consistent with our predictions, we demonstrate that fin spines on the vertical plane (dorsal and anal fins) are associated with a deeper-bodied optimum. Lineages with spines on the horizontal plane (pectoral fins) are associated with a wider-bodied optimum. Optimal body dimensions across lineages without spines paralleling the body dimension match the allometric expectation. Additionally, lineages with longer spines have deeper and wider body dimensions. This evolutionary relationship between fin spines and body dimensions across teleosts reveals functional synergy between these two traits and a potential macroevolutionary signature of predation on the evolutionary dynamics of body shape.     

Sperm competition risk and male genital anatomy: comparative evidence for reduced duration of female sexual receptivity in primates with penile spines

Selection pressures influencing the way in which males stimulate females during copulation are not well understood. In mammals, copulatory stimulation can influence female remating behaviour, both via neuroendocrine mechanisms mediating control of sexual behaviour, and potentially also via effects of minor injury to the female genital tract. Male adaptations to increase copulatory stimulation may therefore function to reduce sperm competition risk by reducing the probability that females will remate. This hypothesis was tested using data for primates to explore relationships between male penile anatomy and the duration of female sexual receptivity. It was predicted that penile spines or relatively large bacula might function to increase copulatory stimulation and hence to reduce the duration of female sexual receptivity. Results of the comparative analyses presented show that, after control for phylogenetic effects, relatively high penile spinosity of male primates is associated with a relatively short duration of female sexual receptivity within the ovarian cycle, although no evidence was found for a similar relationship between baculum length and duration of female sexual receptivity. The findings presented suggest a new potential function for mammalian penile spines in the context of sexual selection, and add to growing evidence that sperm competition and associated sexual conflict are important selection pressures in the evolution of animal genitalia.     

Gene induction during differentiation of human monocytes into dendritic cells: an integrated study at the RNA and protein levels

Changes in gene expression occurring during differentiation of human monocytes into dendritic cells were studied at the RNA and protein levels. These studies showed the induction of several gene classes corresponding to various biological functions. These functions encompass antigen processing and presentation, cytoskeleton, cell signalling and signal transduction, but also an increase in mitochondrial function and in the protein synthesis machinery, including some, but not all, chaperones. These changes put in perspective the events occurring during this differentiation process. On a more technical point, it appears that the studies carried out at the RNA and protein levels are highly complementary.     

Fluticasone impact on airway dendritic cells in smokers: a randomized controlled trial

Background

Myeloid Dendritic cells are key drivers of inflammation in smoke-related lung diseases, whereas plasmacytoid DCs play a crucial role in the defense against infections. Effects of inhaled corticosteroids (ICS) on airway DCs in smokers are unknown.

Methods

In this randomized, double-blind, placebo-controlled clinical trial, 45 active cigarette smokers inhaled placebo, fluticasone or fluticasone plus salmeterol twice daily for 4 weeks. Bronchoalveolar lavage fluid DCs were analyzed using four-color flow cytometry before and after the inhalation period. In addition, fluticasone effects were tested on T-cell proliferation in co-cultures with blood myeloid DCs from smokers.

Results

Inhalation of fluticasone plus salmeterol, but not fluticasone alone or placebo, reduced endobronchial concentrations of myeloid DCs (median decrease: 24%), macrophages (median decrease: 26%) and neutrophils (median decrease: 76%). In contrast, fluticasone reduced plasmacytoid DC concentrations independently of salmeterol. There were no changes in the expression of function-associated surface molecules on myeloid DC (such as CD1a, Langerin, BDCA-1, CD83 or CCR5) in all groups after treatment. Fluticasone (either alone or in combination with salmeterol) suppressed T-cell proliferation in co-cultures with blood myeloid DCs from smokers.

Conclusions

Resistance to ICS monotherapy in smokers might in part be due to lacking effects on airway myeloid DCs, whereas the increased risk for infections during ICS therapy could be attributable to a reduction in plasmacytoid DCs. Combination therapy of fluticasone with salmeterol is associated with a reduction in airway myeloid DCs, but also airway macrophages and neutrophils.

Trial registration

Registered at ClinicalTrials.gov (identifier: {"type":"clinical-trial","attrs":{"text":"NCT00908362","term_id":"NCT00908362"}}NCT00908362) and the European Clinical Trial Database, EudraCT (identifier: 2009-009459-40).     

Phase I/II study of treatment with dendritic cell vaccines in patients with disseminated melanoma

Previous studies have suggested that immunotherapy with dendritic cell (DC) vaccines may be effective in treatment of patients with AJCC stage IV melanoma. We examined this treatment in phase I/II studies in 33 patients with good performance status and low volume disease. Nineteen patients received DCs plus autologous lysates and 14 patients DCs plus peptides from the melanoma antigens MAGE-3.A2, tyrosinase, gp100, and MART-1. Keyhole limpet hemocyanin (KLH) was used as a helper protein and influenza peptide was given as a positive control. DCs were produced from adherent cells in blood lymphocytes (monocytic DCs), grown in IL-4 and GM-CSF without a maturation step. The DCs were injected into inguinal lymph nodes at weekly intervals (×4), 2 weeks (×1), and 4-weekly intervals (×2). There were 3 responses (3 partial responses) and 1 mixed response in the 19 patients treated with DCs plus autologous lysates. No responses were seen in the group treated with DCs plus peptides. Stable disease (defined as no progression over a period of 3 months) was seen in 4 patients in group 1 and 5 patients in group 2. Treatment was not associated with significant side effects. We examined whether DTH skin tests or assays of IFN- cytokine production may be useful predictors of clinical responses. Twenty-two of 30 patients had DTH responses to KLH and 12 of 13 patients had DTH responses to the influenza peptide. Five of 15 DTH responses were seen against autologous lysates. This was strongly correlated with clinical responses. Approximately half the patients had responses to MART-1 peptide and a third to the other melanoma peptides. Similarly, cytokine production assays showed responses to influenza in 7 of 13 patients, and approximately one third of patients had responses to the other peptides. No IFN- responses were seen in 5 patients against their autologous lysates. There was no correlation between assays of IFN- production and clinical responses. The present studies suggest that autologous lysates may be more effective than the melanoma peptides used in the study as the source of antigen for DC vaccines. DTH responses to autologous lysates appear useful predictors of clinical responses, but further work is needed to identify other measures associated with clinical responses.Abbreviations DC dendritic cells - DTH delayed hypersensitivity skin tests - KLH keyhole limpet hemocyanin - CTL cytotoxic T lymphocytes