AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss

Beta amyloid (Abeta), a peptide generated from the amyloid precursor protein (APP) by neurons, is widely believed to underlie the pathophysiology of Alzheimer's disease. Recent studies indicate that this peptide can drive loss of surface AMPA and NMDA type glutamate receptors. We now show that Abeta employs signaling pathways of long-term depression (LTD) to drive endocytosis of synaptic AMPA receptors. Synaptic removal of AMPA receptors is necessary and sufficient to produce loss of dendritic spines and synaptic NMDA responses. Our studies indicate the central role played by AMPA receptor trafficking in Abeta-induced modification of synaptic structure and function.     

Mechanisms of synaptic plasticity: from membrane to intracellular AMPAR trafficking

Brief periods of repetitive neural firing onto adjacent neurons can lead to changes in synaptic plasticity, that is, changes in the make-up of macromolecular complexes located at synapses. This process includes the regulated trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) to synaptic membranes. Little is known, however, about how the AMPARs are regulated before they are shuttled to the membrane. Greger et al. have found that the length of the cytoplasmic tails of constituent subunits of a given AMPAR is determined by editing [at a glutamine (Q) or an arginine (R) codon] near their C termini. Tail length, in turn, dictates whether AMPARs will be retained or quickly released from the endoplasmic reticulum.     

Biomimetic divalent ligands for the acute disruption of synaptic AMPAR stabilization

The interactions of the AMPA receptor (AMPAR) auxiliary subunit Stargazin with PDZ domain-containing scaffold proteins such as PSD-95 are critical for the synaptic stabilization of AMPARs. To investigate these interactions, we have developed biomimetic competing ligands that are assembled from two Stargazin-derived PSD-95/DLG/ZO-1 (PDZ) domain-binding motifs using 'click' chemistry. Characterization of the ligands in vitro and in a cellular FRET-based model revealed an enhanced affinity for the multiple PDZ domains of PSD-95 compared to monovalent peptides. In cultured neurons, the divalent ligands competed with transmembrane AMPAR regulatory protein (TARP) for the intracellular membrane-associated guanylate kinase resulting in increased lateral diffusion and endocytosis of surface AMPARs, while showing strong inhibition of synaptic AMPAR currents. This provides evidence for a model in which the TARP-containing AMPARs are stabilized at the synapse by engaging in multivalent interactions. In light of the prevalence of PDZ domain clusters, these new biomimetic chemical tools could find broad application for acutely perturbing multivalent complexes.     

Interspecific and intraspecific relationships between tooth size and jaw size in primates

The association between mandibular robusticity, postcanine megadontia, and canine reduction in hominins has led to speculation that large and robust jaws might be required to spatially accommodate large canine and molar teeth in hominins and other primates. If so, then variations in mandibular form that are generally regarded as biomechanical adaptations to masticatory demands might instead be incidental effects of functional requirements of tooth support. While the association between large teeth and deep, robust jaws in hominins is well known, the relationship between tooth size and jaw size has not been systematically evaluated in a comparative sample of primates. We evaluate the relationships between molar tooth size, canine tooth size, and mandibular corpus and symphyseal dimensions in a sample of adult anthropoids in interspecific (n=84 species) and intraspecific (n=36 species) contexts. For intraspecific comparisons, tooth size and jaw size are correlated, but for a majority of species this is a function of sexual size dimorphism. Interspecific comparisons lend little direct support to the hypothesis that jaw breadth directly covaries with molar tooth breadth, but they do support the hypothesis that mandibular depth is associated with canine tooth size in males. The latter observation suggests that if there is a causal association between canine size and mandibular depth, it is subject to a threshold effect. In contrast, neither corpus nor symphyseal robusticity, measured as a shape index of breadth/height, are correlated with tooth size. Our results suggest that further studies of the relationship between tooth size and corpus morphology should focus on tooth root size and corpus bony architecture, and that species-specific factors should have a strong impact on such relationships.     

Intra- and interspecific relationships between nest size and immunity

Nest-building behavior has been suggested to represent a postmatingsexually selected signal in passerine birds, an hypothesis thathas received both comparative and experimental support. Becauseselection pressure due to parasites and diseases should be particularlyhigh during nest building, mainly due to energetic costs anddepression of the immune system associated with this reproductivephase, we predicted a positive association between nest-buildingeffort and immunity. Nest-building effort would reflect theability to produce efficient immune responses of builders onlyif individuals with a superior immune system would display exaggeratednest-building effort. We tested this prediction by studyingthe relationship between volume of nest material used for nestconstruction and, at the intraspecific level, estimates of innatehumoral immune response in barn swallows Hirundo rustica. Atthe interspecific level, we used responses to the mitogenicphytohemagglutinin as an indicator of adaptive immune responseof European passerine species. As predicted, we found, aftercontrolling for several potential confounding factors, thatvolume of nest material was positively related to immune responseboth at the intra- and at the interspecific level. Alternativehypotheses explaining the comparative results are discussed.     

A new look at relationships between size at maturity and asymptotic size

Comparative studies have revealed positive correlations between size at maturity and asymptotic size in several taxa with asymptotic growth after maturity. Using a simple growth model, we show that positive correlations between size at maturity and asymptotic size are predicted for different individuals in the same species if growth costs of reproduction are inversely related to size at maturity. Several processes might lead to higher growth costs of reproduction for smaller individuals; these include effects of body size on competition for resources required for breeding, on the space available within the body cavity for food processing in gravid individuals, and on the costs of transporting eggs or young in relation to the total energy budget. We confirm several key elements of the growth model using data from female Iguana iguana lizards, including the novel assumption that instantaneous growth rates of adults of the same length will be positively related to their length at maturity. These analyses suggest a simple and possibly general explanation for positive correlations between size at maturity and asymptotic size within-and perhaps also among-species that continue to grow after maturity.     

Gephyrin expression and clustering affects the size of glutamatergic synaptic contacts

We have recently shown that disrupting the expression and post-synaptic clustering of gephyrin in cultured hippocampal pyramidal cells, by either gephyrin RNAi (RNA interference) or over-expression of a dominant negative gephyrin-enhanced green fluorescent protein (EGFP) fusion protein, leads to decreased number of post-synaptic gephyrin and GABA_A receptor clusters and to reduced GABAergic innervation of these cells. On the other hand, increasing gephyrin expression led to a small increase in the number of gephyrin and GABA_A receptor clusters and to little or no effect on GABAergic innervation. We are now reporting that altering gephyrin expression and clustering affects the size but not the density of glutamatergic synaptic contacts. Knocking down gephyrin with gephyrin RNAi, or preventing gephyrin clustering by over-expression of the dominant negative gephyrin-enhanced green fluorescent protein fusion protein, leads to larger post-synaptic PSD-95 clusters and larger pre-synaptic glutamatergic terminals. On the other hand, over-expression of gephyrin leads to slightly smaller PSD-95 clusters and pre-synaptic glutamatergic terminals. The change in size of PSD-95 clusters were accompanied by a parallel change in the size of NR2-NMDA receptor clusters. It is concluded that the levels of expression and clustering of gephyrin, a protein that concentrates at the post-synaptic complex of the inhibitory synapses, not only has homotypic effects on GABAergic synaptic contacts, but also has heterotypic effects on glutamatergic synaptic contacts. We are proposing that gephyrin is a counterpart of the post-synaptic glutamatergic scaffold protein PSD-95 in regulating the number and/or size of the excitatory and inhibitory synaptic contacts.     

Multi-scale relationships between numbers and size in the evolution of arthropod body features

Size-related changes of form in animals with periodically patterned body axes and post-embryonic growth discontinuously obtained throughout a series of moulting episodes cannot be accounted for by allometry alone. We address here the relationships between body size and number and size of appropriately selected structural units (e.g., segments), which may more or less closely approximate independent developmental units, or unitary targets of selection, or both. Distinguishing between units fundamentally involving one cell only or a small and fixed number of cells (e.g., the ommatidia in a compound eye), and units made of an indeterminate number of cells (e.g., trunk segments), we analyze and discuss a selection of body features of either kind, both in ontogeny and in phylogeny, through a review of current literature and meta-analyses of published and unpublished data. While size/number relationships are too diverse to allow easy generalizations, they provide conspicuous examples of the complex interplay of selective forces and developmental constraints that characterizes the evolution of arthropod body patterning.     

Modulation of glutamate mobility reveals the mechanism underlying slow-rising AMPAR EPSCs and the diffusion coefficient in the synaptic cleft

Fast- and slow-rising AMPA receptor-mediated EPSCs occur at central synapses. Fast-rising EPSCs are thought to be mediated by rapid local release of glutamate. However, two controversial mechanisms have been proposed to underlie slow-rising EPSCs: prolonged local release of transmitter via a fusion pore, and spillover of transmitter released rapidly from distant sites. We have investigated the mechanism underlying slow-rising EPSCs and the diffusion coefficient of glutamate in the synaptic cleft (Dglut) at cerebellar mossy fiber-granule cell synapses using a combination of diffusion modeling and patch-clamp recording. Simulations show that modulating Dglut has different effects on the peak amplitudes and time courses of EPSCs mediated by these two mechanisms. Slowing diffusion with the macromolecule dextran slowed slow-rising EPSCs and had little effect on their amplitude, indicating that glutamate spillover underlies these currents. Our results also suggest that under control conditions Dglut is approximately 3-fold lower than in free solution.     

Ladybird egg cluster size: relationships between species, oviposition substrate and cannibalism

The success or not of ladybirds as biological control agents is dependent on both their foraging behaviour and their individual survival rates. The former is a function of the habitats they utilise; the latter, a consequence of their reproductive strategy. Egg clustering was investigated in two ladybird species, Aphidecta obliterata, a conifer specialist, and Adalia bipunctata, an arboreal woodland generalist. The effect of oviposition substrate (filter papers vs. spruce needles) on clutch size and oviposition preference was also tested. Adalia bipunctata laid significantly more eggs than A. obliterata. The size of egg clusters laid by the two coccinellids varied between species and substrate types. Adalia bipunctata laid larger egg clusters than A. obliterata, with batches reaching a maximum size of 32 eggs on spruce and 41 eggs on paper, while those of A. obliterata contained a maximum of 5 eggs on spruce and 9 eggs on paper. Of the clusters laid by A. obliterata, 18.6% of those on paper and 21.4% of those on spruce contained only a single egg, whereas a minimum of two eggs per cluster were laid by A. bipunctata. Smaller clusters were laid on the spruce cuttings by both species when compared with those laid on the filter paper, but A. obliterata laid significantly more eggs on spruce than on the filter paper (77% vs. 23%), whilst A. bipunctata laid significantly more eggs on the filter paper (91%). It is suggested that coccinellid eggs are more likely to be washed off spruce needles than broad leaves and that, by laying smaller egg clusters on spruce, A. obliterata reduces this risk. Adalia bipunctata usually lays its eggs on the underside of broad leaved trees and thus does not face this risk and thus can lay larger egg clusters. No differences in cannibalism rates were found between the two species. These findings have implications for the use of ladybirds as biological control agents in spruce forests.     

Geometrical constraints in the scaling relationships between genome size, cell size and cell cycle length in herbaceous plants

Plant nuclear genome size (GS) varies over three orders of magnitude and is correlated with cell size and growth rate. We explore whether these relationships can be owing to geometrical scaling constraints. These would produce an isometric GS-cell volume relationship, with the GS-cell diameter relationship with the exponent of 1/3. In the GS-cell division relationship, duration of processes limited by membrane transport would scale at the 1/3 exponent, whereas those limited by metabolism would show no relationship. We tested these predictions by estimating scaling exponents from 11 published datasets on differentiated and meristematic cells in diploid herbaceous plants. We found scaling of GS-cell size to almost perfectly match the prediction. The scaling exponent of the relationship between GS and cell cycle duration did not match the prediction. However, this relationship consists of two components: (i) S phase duration, which depends on GS, and has the predicted 1/3 exponent, and (ii) a GS-independent threshold reflecting the duration of the G1 and G2 phases. The matches we found for the relationships between GS and both cell size and S phase duration are signatures of geometrical scaling. We propose that a similar approach can be used to examine GS effects at tissue and whole plant levels.     

Anurans as prey: an exploratory analysis and size relationships between predators and their prey

The vertebrate predators of post-metamorphic anurans were quantified and the predator–prey relationship was investigated by analysing the relative size of invertebrate predators and anurans. More than 100 vertebrate predators were identified (in more than 200 reports) and classified as opportunistic, convenience, temporary specialized and specialized predators. Invertebrate predators were classified as solitary non-venomous, venomous and social foragers according to 333 reviewed reports. Each of these categories of invertebrate predators was compared with the relative size of the anurans, showing an increase in the relative size of the prey when predators used special predatory tactics. The number of species and the number of families of anurans that were preyed upon did not vary with the size of the predator, suggesting that prey selection was not arbitrary and that energetic constraints must be involved in this choice. The relatively low predation pressure upon brachycephalids was related to the presence of some defensive strategies of its species. This compounding review can be used as the foundation for future advances in vertebrate predator–prey interactions.     

Interspecific relationships between egg size and the level of parental investment per offspring in echinoderms

The relationship between the size of an egg and its energy content was analyzed using published data for 47 species of echinoderms. Scaling relationships were evaluated for all species, as well as for subsets of the species, based on mode of development. Regressions were calculated using linear, power function, full allometric, and second-order polynomial models. The full allometric model is preferred because it is relatively simple and the most general. Among these species of echinoderms, larger eggs contain more energy. Egg energy content scales isometrically across a wide range of egg sizes both among and within different modes of development. The only exception is among species with feeding larval development, where there does not seem to be a clear scaling relationship. In most cases, the regressions were statistically significant and explained a very large proportion of the variance in energy content. However, there were wide confidence intervals around the estimated regression parameters. In all cases, the predictive power of the regression was poor, requiring large differences in egg size to yield significantly different predictions of energy content. Consequently, egg size is of limited value for the quantitative prediction of egg energy content and should be used with caution in life-history studies.     

The relationships between abundance, range size and niche breadth in Central European tree species

Aim  Range size and niche breadth have been found to be positively related to abundance in many plant and animal groups. We tested these two relationships for the tree species flora of Central Europe; that is, for all 25 species that have their distribution centre in this region.
Location  Eurasia, with a focus on Central Europe.
Methods  We devised an abundance and niche variable classification system to transform the existing literature data into a semi-quantitative assessment of abundance and niche breadth (in terms of soil chemical and physical variables, and temperature) for each of the 25 tree species. Regression analyses between abundance, range size and niche breadth were conducted for the entire species sample and for subsets of species defined by their ecology or phylogeny.
Results  The relationship between abundance in the distribution centre and range size was weak for the Central European tree species. However, significant abundance–range size relationships were found for phylogenetically or ecologically more homogenous species groups (for example for trees of the order Rosales and for mid-successional tree species). Realized niche breadth was positively related to range size in the case of temperature, but not for soil-related variables. No relationship existed between niche breadth and abundance in the distribution centre.
Main conclusions  We hypothesize that the weak relationship between abundance and range size is primarily a consequence of substantial ecological and phylogenetic heterogeneity within this rather species-poor assemblage. The positive relationship between realized temperature niche breadth and range size emphasizes the strong influence of climatic variables on plant distribution patterns over continental or global scales.     

Correction for non-linear relationships between root size and short term Pi uptake in genotype comparisons

Variation in phosphate (Pi) absorption rates, root length and root mass was investigated in 25 genotypes or inbred lines of Arabidopsis thaliana (L.) Heynh. All variables differed among lines (P<0.0001), and larger plants with larger roots and shoots had faster Pi uptake rates (influx) (P<0.0001). Within genotypes, influx was non-linearly related to root size. Increases in influx were not directly proportional to increases in root size; with a doubling in root length or biomass, there was only a 1.30 or 1.27 concomitant increase in influx, respectively. Because inbred lines are genetically homogeneous, this within-genotype pattern was random, and not genetically based.Influx has traditionally been standardized for variation in plant size by dividing by root length or biomass. This assumes a linear relationship between influx and root size. As uptake rate was non-linearly dependent on root size in A. thaliana, this resulted in a spurious negative correlation between influx per cm or mg root and root length or biomass. We present a general method that standardizes influx for variation in root size within genetically homogenous genotypes. This method determines and corrects for random non-linear relationships between influx and root size. In A. thaliana, influx per unit root length or biomass differed among lines (P<0.0001), but these differences did not correlate with root length or biomass. These data contradict the common interpretation in previous literature that species or cultivars with small roots have evolved greater influx per unit size of root.     

Some size relationships in phytoflagellate motility

Data from the literature are used to assess some hypothesised adaptive advantages of the flagellate life form among phytoplankton. Possible advantages include increased nutrient uptake by movement through a homogeneous medium as opposed to exploitation of spatial hetrogeneity of the environment. Maximal migrational amplitudes and maximal swimming velocities of phytoflagellates were compared to body size. Both were found to increase with size. Relative amplitudes and relative velocities, however, were found to decrease with size. Hydrophysical considerations show that additional gain of nutrients by swimming through a homogeneous medium is only minimal for small flagellates at their attainable swimming velocities. It is suggested that exploitation of environmental heterogeneity in nutrient distribution may be one of the most important advantages for flagellates over coccoid algae.     

The synaptic relationships between the primary afferent terminals and the cuneo-thalamic relay neurons in the rat cuneate nucleus

In order to establish the synaptic relationship between the primary afferent terminals and the cuneothalamic relay neurons in the cuneate nucleus, the combined retrograde transport of horseradish peroxidase (HRP) and experimental degeneration have been applied in the young adult albino rats. 10 to 30% HRP was injected contralaterally (0.5 microliter) in the ventrobasal thalamic nucleus and multiple dorsal rhizotomies (C5 to T1) in the cervicothoracic dorsal roots were performed on the side ipsilateral to the cuneate nucleus. The results showed that: The cuneo-thalamic relay (CTN) neurons were the major neuronal type of the nucleus. More than 55% of neurons have been labelled. These neurons were 18-30 micron X 15-25 micron in sizes. They distributed in the whole rostrocaudal extent of the nucleus, particularly dense in the middle portion. The cells varied from round, oval, spindle to multipolar in shapes. They were rich in cytoplasmic organelles and had well-developed roughed endoplasmic reticulum. Their nucleus was either centrally or eccentrically located and was rather regular. The HRP-positive granules were randomly distribute in the perikaryon, dendrites and initial segment of the axons; At least three types of the experimental degeneration of the primary afferent terminals (PAT) were observed in the cuneate nucleus two to three days after dorsal rhizotomy, namely, electron-dense, granular and neurofilamentous. These PAT were mostly large and contained round vesicles. They were commonly found within synaptic complex, in which they were presynaptic to dendrites of various sizes, and were themselves postsynaptic to smaller axon terminals containing flattened vesicles. Degenerating PAT forming isolated synapses were less commonly seen; The PAT in the synaptic complex were directly presynaptic to the dendrites originating from the CTN neurons. The dendrites forming PAT-CTN synases were of large and medium-sized. The PAT did not form direct axo-somatic synapses with the somata of CTN or of any other cell types in the cuneate nucleus.     

Prenatal cocaine exposure increases synaptic localization of a neuronal RasGEF, GRASP-1 via hyperphosphorylation of AMPAR anchoring protein, GRIP

Prenatal cocaine exposure causes sustained phosphorylation of the synaptic anchoring protein, glutamate receptor interacting protein (GRIP1/2), preventing synaptic targeting of the GluR2/3-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs; J. Neurosci. 29: 6308-6319, 2009). Because overexpression of GRIP-associated neuronal rasGEF protein (GRASP-1) specifically reduces the synaptic targeting of AMPARs, we hypothesized that prenatal cocaine exposure enhances GRASP-1 synaptic membrane localization leading to hyper-activation of ras family proteins and heightened actin polymerization. Our results show a markedly increased GRIP1-associated GRASP-1 content with approximately 40% reduction in its rasGEF activity in frontal cortices (FCX) of 21-day-old (P21) prenatal cocaine-exposed rats. This cocaine effect is the result of a persistent protein kinase C (PKC)- and downstream Src tyrosine kinase-mediated GRIP phosphorylation. The hyperactivated PKC also increased membrane-associated GRASP-1 and activated small G-proteins RhoA, cdc42/Rac1 and Rap1 as well as filamentous actin (F-actin) levels without an effect on the phosphorylation state of actin. Since increased F-actin facilitates protein transport, our results suggest that increased GRASP-1 synaptic localization in prenatal cocaine-exposed brains is an adaptive response to restoring the synaptic expression of AMPA-GluR2/3. Our earlier data demonstrated that persistent PKC-mediated GRIP phosphorylation reduces GluR2/3 synaptic targeting in prenatal cocaine-exposed brains, we now show that the increased GRIP-associated GRASP-1 may contribute to the reduction in GluR2/3 synaptic expression and AMPAR signaling defects.