Postsynaptic Kainate Receptor Recycling and Surface Expression Are Regulated by Metabotropic Autoreceptor Signalling

Kainate receptors (KARs) play fundamentally important roles in controlling synaptic function and regulating neuronal excitability. Postsynaptic KARs contribute to excitatory neurotransmission but the molecular mechanisms underlying their activity‐dependent surface expression are not well understood. Strong activation of KARs in cultured hippocampal neurons leads to the downregulation of postsynaptic KARs via endocytosis and degradation. In contrast, low‐level activation augments postsynaptic KAR surface expression. Here, we show that this increase in KARs is due to enhanced recycling via the recruitment of Rab11‐dependent, transferrin‐positive endosomes into spines. Dominant‐negative Rab11 or the recycling inhibitor primaquine prevents the kainate‐evoked increase in surface KARs. Moreover, we show that the increase in surface expression is mediated via a metabotropic KAR signalling pathway, which is blocked by the protein kinase C inhibitor chelerythrine, the calcium chelator BAPTA and the G‐protein inhibitor pertussis toxin. Thus, we report a previously uncharacterized positive feedback system that increases postsynaptic KARs in response to low‐ or moderate‐level agonist activation and can provide additional flexibility to synaptic regulation.      

The spatial scaling of habitat selection by African elephants

1. Understanding and accurately predicting the spatial patterns of habitat use by organisms is important for ecological research, biodiversity conservation and ecosystem management. However, this understanding is complicated by the effects of spatial scale, because the scale of analysis affects the quantification of species-environment relationships. 2. We therefore assessed the influence of environmental context (i.e. the characteristics of the landscape surrounding a site), varied over a large range of scales (i.e. ambit radii around focal sites), on the analysis and prediction of habitat selection by African elephants in Kruger National Park, South Africa. 3. We focused on the spatial scaling of the elephants' response to their main resources, forage and water, and found that the quantification of habitat selection strongly depended on the scales at which environmental context was considered. Moreover, the inclusion of environmental context at characteristic scales (i.e. those at which habitat selectivity was maximized) increased the predictive capacity of habitat suitability models. 4. The elephants responded to their environment in a scale-dependent and perhaps hierarchical manner, with forage characteristics driving habitat selection at coarse spatial scales, and surface water at fine spatial scales. 5. Furthermore, the elephants exhibited sexual habitat segregation, mainly in relation to vegetation characteristics. Male elephants preferred areas with high tree cover and low herbaceous biomass, whereas this pattern was reversed for female elephants. 6. We show that the spatial distribution of elephants can be better understood and predicted when scale-dependent species-environment relationships are explicitly considered. This demonstrates the importance of considering the influence of spatial scale on the analysis of spatial patterning in ecological phenomena.     

Urinary bisphenol a concentration and angiography-defined coronary artery stenosis

Background

Bisphenol A is widely used in food and drinks packaging. There is evidence of associations between raised urinary bisphenol A (uBPA) and increased incidence of reported cardiovascular diagnoses.

Methodology/Principal Findings

To estimate associations between BPA exposure and angiographically graded coronary atherosclerosis. 591 patients participating in The Metabonomics and Genomics in Coronary Artery Disease (MaGiCAD) study in Cambridgeshire UK, comparing urinary BPA (uBPA) with grades of severity of coronary artery disease (CAD) on angiography. Linear models were adjusted for BMI, occupational social class and diabetes status. Severe (one to three vessel) CAD was present in 385 patients, 86 had intermediate disease (n = 86) and 120 had normal coronary arteries. The (unadjusted) median uBPA concentration was 1.28 ng/mL with normal coronary arteries, and 1.53 ng/mL with severe CAD. Compared to those with normal coronary arteries, uBPA concentration was significantly higher in those with severe CAD (OR per uBPA SD = 5.96 ng/ml OR = 1.43, CI 1.03 to 1.98, p = 0.033), and near significant for intermediate disease (OR = 1.69, CI 0.98 to 2.94, p = 0.061). There was no significant uBPA difference between patients with severe CAD (needing surgery) and the remaining groups combined.

Conclusions/Significance

BPA exposure was higher in those with severe coronary artery stenoses compared to those with no vessel disease. Larger studies are needed to estimate true dose response relationships. The mechanisms underlying the association remain to be established.     

First frozen repository for the Great Barrier Reef coral created

To build new tools for the continued protection and propagation of coral from the Great Barrier Reef (GBR), an international group of coral and cryopreservation scientists known as the Reef Recovery Initiative joined forces during the November 2011 mass-spawning event. The outcome was the creation of the first frozen bank for Australian coral from two important GBR reef-building species, Acropora tenuis and Acropora millepora. Approximately 190 frozen samples each with billions of cells were placed into long-term storage. Sperm cells were successfully cryopreserved, and after thawing, samples were used to fertilize eggs, resulting in functioning larvae. Additionally, developing larvae were dissociated, and these pluripotent cells were cryopreserved and viable after thawing. Now, we are in a unique position to move our work from the laboratory to the reefs to develop collaborative, practical conservation management tools to help secure Australia's coral biodiversity.     

Bidirectional regulation of kainate receptor surface expression in hippocampal neurons

Kainate receptors (KARs) are crucial for the regulation of both excitatory and inhibitory neurotransmission, but little is known regarding the mechanisms controlling KAR surface expression. We used super ecliptic pHluorin (SEP)-tagged KAR subunit GluR6a to investigate real-time changes in KAR surface expression in hippocampal neurons. Sindbis virus-expressed SEP-GluR6 subunits efficiently co-assembled with native KAR subunits to form heteromeric receptors. Diffuse surface-expressed dendritic SEP-GluR6 is rapidly internalized following either N-methyl-d-aspartate or kainate application. Sustained kainate or transient N-methyl-d-aspartate application resulted in a slow decrease of base-line surface KAR levels. Surprisingly, however, following the initial loss of surface receptors, a short kainate application caused a long lasting increase in surface-expressed KARs to levels significantly greater than those prior to the agonist challenge. These data suggest that after initial endocytosis, transient agonist activation evokes increased KAR exocytosis and reveal that KAR surface expression is bidirectionally regulated. This process may provide a mechanism for hippocampal neurons to differentially adapt their physiological responses to changes in synaptic activation and extrasynaptic glutamate concentration.     

Effect of sympathectomy and demedullation on increased myenteric and dorsal vagal complex Fos-like immunoreactivity by cholecystokinin-8

Chemical sympathectomy with daily, intraperitoneal (IP) injections of guanethidine sulfate to adult rats, attenuated myenteric, but not dorsal vagal complex (DVC) Fos-like immunoreactivity (Fos-LI) by cholecystokinin-8 (CCK). This technique destroys only 60-70% of the sympathetic neurons, and spares the hormonal source of catecholamines, the adrenal medulla. The goal of the current study is to evaluate the effect of complete sympathectomy or destroying 100% of the sympathetic neurons by injecting guanethidine to 1-day-old pups (40 mg/kg daily for 5 weeks), and surgically removing the adrenal medulla. In the DVC, demedullation and sympathectomy-demedullation increased Fos-LI by CCK in the area postrema and nucleus of the solitary tract, but sympathectomy-demedullation increased it only in the area postrema. In the myenteric plexus, sympathectomy increased this response in the duodenum, and demedullation increased it in the duodenum and jejunum. On the other hand, sympathectomy-demedullation attenuated myenteric Fos-LI in the jejunum. These results indicate that catecholamines may play an inhibitory role on the activation of the DVC neurons by CCK. In the myenteric neurons, however, catecholamines may have both inhibitory and excitatory roles depending on the level of the intestine e.g., duodenum vs. jejunum. This may also indicate that CCK activates the enteric neurons by different mechanisms or through different pathways.     

Supplementation with antioxidants and folinic acid for children with Down’s syndrome: randomised controlled trial

Objectives To assess whether supplementation with antioxidants, folinic acid, or both improves the psychomotor and language development of children with Down’s syndrome.Design Randomised controlled trial with two by two factorial design.Setting Children living in the Midlands, Greater London, and the south west of England.Participants 156 infants aged under 7 months with trisomy 21.Intervention Daily oral supplementation with antioxidants (selenium 10 μg, zinc 5 mg, vitamin A 0.9 mg, vitamin E 100 mg, and vitamin C 50 mg), folinic acid (0.1 mg), antioxidants and folinic acid combined, or placebo.Main outcome measures Griffiths developmental quotient and an adapted MacArthur communicative development inventory 18 months after starting supplementation; biochemical markers in blood and urine at age 12 months.Results Children randomised to antioxidant supplements attained similar developmental outcomes to those without antioxidants (mean Griffiths developmental quotient 57.3 v 56.1; adjusted mean difference 1.2 points, 95% confidence interval −2.2 to 4.6). Comparison of children randomised to folinic acid supplements or no folinic acid also showed no significant differences in Griffiths developmental quotient (mean 57.6 v 55.9; adjusted mean difference 1.7, −1.7 to 5.1). No between group differences were seen in the mean numbers of words said or signed: for antioxidants versus none the ratio of means was 0.85 (95% confidence interval 0.6 to 1.2), and for folinic acid versus none it was 1.24 (0.87 to 1.77). No significant differences were found between any of the groups in the biochemical outcomes measured. Adjustment for potential confounders did not appreciably change the results.Conclusions This study provides no evidence to support the use of antioxidant or folinic acid supplements in children with Down’s syndrome.Trial registration Clinical trials {"type":"clinical-trial","attrs":{"text":"NCT00378456","term_id":"NCT00378456"}}NCT00378456.