Homomeric Q/R edited AMPA receptors conduct when desensitized

Desensitization is a canonical property of ligand-gated ion channels, causing progressive current decline in the continued presence of agonist. AMPA-type glutamate receptors, which mediate fast excitatory signaling throughout the brain, exhibit profound desensitization. Recent cryo-EM studies of AMPAR assemblies show their ion channels to be closed in the desensitized state. Here we report the surprising finding that homomeric Q/R edited AMPARs still allow ions to flow when the receptors are desensitized. GluA2(R) expressed alone, or with auxiliary subunits (γ-2, γ-8 or GSG1L), generates large steady-state currents and anomalous current-variance relationships. Using fluctuation analysis, single-channel recording, and kinetic modeling we demonstrate that the steady-state current is mediated predominantly by ‘conducting desensitized’ receptors. When combined with crystallography this unique functional readout of a hith-erto silent state enabled us to examine cross-linked cysteine mutants to probe the conformation of the desensitized ligand binding domain of functioning AMPAR complexes within the plasma membrane

Synapse Type-Dependent Expression of Calcium-Permeable AMPA Receptors

Calcium-permeable (CP) AMPA-type glutamate receptors (AMPARs) are known to mediate synaptic plasticity in several different interneuron (IN) types. Recent evidence suggests that CP-AMPARs are synapse-specifically expressed at excitatory connections onto a subset of IN types in hippocampus and neocortex. For example, CP-AMPARs are found at connections from pyramidal cells (PCs) to basket cells (BCs), but not to Martinotti cells (MCs). This synapse type-specific expression of CP-AMPARs suggests that synaptic dynamics as well as learning rules are differentially implemented in local circuits and has important implications not just in health but also in disease states such as epilepsy

Synapse-specific expression of calcium-permeable AMPA receptors in neocortical layer 5

In the hippocampus, calcium‐permeable AMPA receptors have been found in a restricted subset of neuronal types that inhibit other neurons, although their localization in the neocortex is less well understood. In the present study, we looked for calcium‐permeable AMPA receptors in two distinct populations of neocortical inhibitory neurons: basket cells and Martinotti cells. We found them in the former but not in the latter. Furthermore, in basket cells, these receptors were associated with particularly fast responses. Computer modelling predicted (and experiments verified) that fast calcium‐permeable AMPA receptors enable basket cells to respond rapidly, such that they promptly inhibit neighbouring cells and shut down activity. The results obtained in the present study help our understanding of pathologies such as stroke and epilepsy that have been associated with disordered regulation of calcium‐permeable AMPA receptors

Developing a framework of Quaternary dune accumulation in the northern Rub' al-Khali, Arabia

Located at the crossroads between Africa and Eurasia, Arabia occupies a pivotal position for human migration and dispersal during the Late Pleistocene. Deducing the timing of humid and arid phases is critical to understanding when the Rub' al-Khali desert acted as a barrier to human movement and settlement. Recent geological mapping in the northern part of the Rub' al-Khali has enabled the Quaternary history of the region to be put into a regional stratigraphical framework. In addition to the active dunes, two significant palaeodune sequences have been identified. Dating of key sections has enabled a chronology of dune accretion and stabilisation to be determined. In addition, previously published optically stimulated luminescence (OSL) dates have been put in their proper stratigraphical context, from which a record of Late Pleistocene dune activity can be constructed. The results indicate the record of dune activity in the northern Rub' al-Khali is preservation limited and is synchronous with humid events driven by the incursion of the Indian Ocean monsoon

Scaling in high-temperature superconductors

A Hartree approximation is used to study the interplay of two kinds of scaling which arise in high-temperature superconductors, namely critical-point scaling and that due to the confinement of electron pairs to their lowest Landau level in the presence of an applied magnetic field. In the neighbourhood of the zero-field critical point, thermodynamic functions scale with the scaling variable $(T-T_{c2}(B))/B^{1/2\nu}$, which differs from the variable $(T - T_c(0))/B^{1/2\nu}$ suggested by the gaussian approximation. Lowest-Landau-level (LLL) scaling occurs in a region of high field surrounding the upper critical field line but not in the vicinity of the zero-field transition. For YBaCuO in particular, a field of at least 10 T is needed to observe LLL scaling. These results are consistent with a range of recent experimental measurements of the magnetization, transport properties and, especially, the specific heat of high-$T_c$ materials.Comment: 22 pages + 1 figure appended as postscript fil

Prevalence of chronic kidney disease in Asia: A systematic review and analysis

Introduction The burden of chronic kidney disease (CKD) is growing rapidly around the world. However, there is limited information on the overall regional prevalence of CKD, as well as the variations in national prevalence within Asia. We aimed to consolidate available data and quantify estimates of the CKD burden in this region. Methods We systematically searched MEDLINE, Embase and Google Scholar for observational studies and contacted national experts to estimate CKD prevalence in countries of Asia (Eastern, Southern and South Eastern Asia). CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 or the presence of proteinuria. For countries without reported data, we estimated CKD prevalence using agglomerative average-linkage hierarchical clustering, based on country-level risk factors and random effects meta-analysis within clusters. Published CKD prevalence data were obtained for 16 countries (of the 26 countries in the region) and estimates were made for 10 countries. Results There was substantial variation in overall and advanced (eGFR <30 mL/min/1.73 m 2) CKD prevalence (range: 7.0%-34.3% and 0.1%-17.0%, respectively). Up to an estimated 434.3 million (95% CI 350.2 to 519.7) adults have CKD in Asia, including up to 65.6 million (95% CI 42.2 to 94.9) who have advanced CKD. The greatest number of adults living with CKD were in China (up to 159.8 million, 95% CI 146.6 to 174.1) and India (up to 140.2 million, 95% CI 110.7 to 169.7), collectively having 69.1% of the total number of adults with CKD in the region. Conclusion The large number of people with CKD, and the substantial number with advanced CKD, show the need for urgent collaborative action in Asia to prevent and manage CKD and its complications

Transient developmental imbalance of cortical interneuron subtypes presages long-term changes in behavior

Cortical GABAergic interneurons are generated in large numbers in the ganglionic eminences and migrate into the cerebral cortex during embryogenesis. At early postnatal stages, during neuronal circuit maturation, autonomous and activity-dependent mechanisms operate within the cortex to adjust cell numbers by eliminating naturally occurring neuron excess. Here, we show that when cortical interneurons are generated in aberrantly high numbers—due to a defect in precursor cell proliferation during embryogenesis—extra parvalbumin interneurons persist in the postnatal mouse cortex during critical periods of cortical network maturation. Even though cell numbers are subsequently normalized, behavioral abnormalities remain in adulthood. This suggests that timely clearance of excess cortical interneurons is critical for correct functional maturation of circuits that drive adult behavior

Neuropharmacological effects of deltamethrin in rats

This study examined the effect of deltamethrin on some of the neuropharmacological paradigms in a rat brain such as the motor co-ordination test using a rotarod, the pentobarbitone-induced sleeping time and pentylenetetrazole (PTZ)-induced convulsion as well as the gamma aminobutyric acid (GABA) level. Albino Wistar rats were used as the experimental animals. Different neuropharmacological paradigms such as the motor co-ordination by the rotarod, pentobarbitone-induced sleeping time and the PTZ-induced convulsion were examined after administering deltamethrin orally at two doses, 150 mg/kg (LD50) and 15 mg/kg (1/10 LD50). The GABA level in the rat brain was estimated by HPLC after a single oral dose of 150mg/kg deltamethrin. Deltamethrin significantly reduced the motor coordination, decreased the onset time and increased the sleeping time duration induced by pentobarbitone. In addition, it also decreased the onset time and increased the duration of convulsions induced by PTZ at 150 mg/kg (LD50) and 15 mg/kg (1/10 LD50), respectively. Further deltamethrin administration decreased the GABA levels in the cerebellum as well as in the whole brain (except the cerebellum) significantly at the LD50 dose level. There was some correlation between the effect of deltamethrin on the central GABA levels and its neuropharmacological effects

Stonehenge: a unique Late Cretaceous phosphatic Chalk geology: implications for sea-level, climate and tectonics and impact on engineering and archaeology

Ground investigations for the A303 Stonehenge Tunnels revealed a unique and complex Chalk geology including the presence of the thickest (>20 m thick), and previously unknown phosphatic chalks in England, partly filling fault controlled erosional channels. The use of natural gamma-ray borehole logs to determine the presence and thickness of the phosphatic deposits is of particular value and combined with the lithostratigraphy, macrofossil and nannofossil biostratigraphy from cores has, for the first time, accurately constrained the Coniacian to Santonian age and the lenticular geometry of such deposits. Four phosphatic chalk events between 88.5–86.5 Ma are recognised associated with synsedimentary faulting. We suggest a causal link between tectonics, subsidence and channel-formation, phosphatisation events, pulses of oceanic upwelling on a frequency of about 0.5 million years to mantle-controlled plate tectonic episodes. The implications of this geology for construction of the A303 and the archaeology of the area are discussed