559 research outputs found
Activity-Dependent mRNA Splicing Controls ER Export and Synaptic Delivery of NMDA Receptors
AbstractActivity-dependent targeting of NMDA receptors (NMDARs) is a key feature of synapse formation and plasticity. Although mechanisms for rapid trafficking of glutamate receptors have been identified, the molecular events underlying chronic accumulation or loss of synaptic NMDARs have remained unclear. Here we demonstrate that activity controls NMDAR synaptic accumulation by regulating forward trafficking at the endoplasmic reticulum (ER). ER export is accelerated by the alternatively spliced C2Ⲡdomain of the NR1 subunit and slowed by the C2 splice cassette. This mRNA splicing event at the C2/C2Ⲡsite is activity dependent, with C2Ⲡvariants predominating upon activity blockade and C2 variants abundant with increased activity. The switch to C2Ⲡaccelerates NMDAR forward trafficking by enhancing recruitment of nascent NMDARs to ER exit sites via binding of a divaline motif within C2Ⲡto COPII coats. These results define a novel pathway underlying activity-dependent targeting of glutamate receptors, providing an unexpected mechanistic link between activity, mRNA splicing, and membrane trafficking during excitatory synapse modification
Activity-Dependent Modulation of Synaptic AMPA Receptor Accumulation
AbstractBoth theoretical and experimental work have suggested that central neurons compensate for changes in excitatory synaptic input in order to maintain a relatively constant output. We report here that inhibition of excitatory synaptic transmission in cultured spinal neurons leads to an increase in mEPSC amplitudes, accompanied by an equivalent increase in the accumulation of AMPA receptors at synapses. Conversely, increasing excitatory synaptic activity leads to a decrease in synaptic AMPA receptors and a decline in mEPSC amplitude. The time course of this synaptic remodeling is slow, similar to the metabolic half-life of neuronal AMPA receptors. Moreover, inhibiting excitatory synaptic transmission significantly prolongs the half-life of the AMPA receptor subunit GluR1, suggesting that synaptic activity modulates the size of the mEPSC by regulating the turnover of postsynaptic AMPA receptors
Catalog of 199 register-based definitions of chronic conditions
Introduction: The aim of the current study was to present and discuss a broad range of register-based definitions of chronic conditions for use in register research, as well as the challenges and pitfalls when defining chronic conditions by the use of registers. Materials and methods: The definitions were defined based on information from nationwide Danish public healthcare registers. Medical and epidemiological specialists identified and grouped relevant diagnosis codes that covered chronic conditions, using the International Classification System version 10 (ICD-10). Where relevant, prescription and other healthcare data were also used to define the chronic conditions. Results: We identified 199 chronic conditions and subgroups, which were divided into four groups according to a medical judgment of the expected duration of the conditions, as follows. Category I: Stationary to progressive conditions (maximum register inclusion time of diagnosis since the start of the register in 1994). Category II: Stationary to diminishing conditions (10 years of register inclusion after time of diagnosis). Category III: Diminishing conditions (5 years of register inclusion after time of diagnosis). Category IV: Borderline conditions (2 years of register inclusion time following diagnosis). The conditions were primarily defined using hospital discharge diagnoses; however, for 35 conditions, including common conditions such as diabetes, chronic obstructive lung disease and allergy, more complex definitions were proposed based on record linkage between multiple registers, including registers of prescribed drugs and use of general practitionersâ services. Conclusions: This study provided a catalog of register-based definitions for chronic conditions for use in healthcare planning and research, which is, to the authorsâ knowledge, the largest currently compiled in a single study
Polarized Secretory Trafficking Directs Cargo for Asymmetric Dendrite Growth and Morphogenesis
SummaryProper growth of dendrites is critical to the formation of neuronal circuits, but the cellular machinery that directs the addition of membrane components to generate dendritic architecture remains obscure. Here, we demonstrate that post-Golgi membrane trafficking is polarized toward longer dendrites of hippocampal pyramidal neurons in vitro and toward apical dendrites in vivo. Small Golgi outposts partition selectively into longer dendrites and are excluded from axons. In dendrites, Golgi outposts concentrate at branchpoints where they engage in post-Golgi trafficking. Within the cell body, the Golgi apparatus orients toward the longest dendrite, and this Golgi polarity precedes asymmetric dendrite growth. Manipulations that selectively block post-Golgi trafficking halt dendrite growth in developing neurons and cause a shrinkage of dendrites in mature pyramidal neurons. Further, disruption of Golgi polarity produces neurons with symmetric dendritic arbors lacking a single longest principal dendrite. These results define a novel polarized organization of neuronal secretory trafficking and demonstrate a mechanistic link between directed membrane trafficking and asymmetric dendrite growth
A Spectroscopic Survey of a Sample of Active M Dwarfs
A moderate resolution spectroscopic survey of Fleming's sample of 54 X-ray
selected M dwarfs with photometric distances less than 25 pc is presented.
Radial and rotation velocities have been measured by fits to the H-alpha
profiles. Radial velocities have been measured by cross correlation. Artificial
broadening of an observed spectrum has produced a relationship between H-alpha
FWHM and rotation speed, which we use to infer rotation speeds for the entire
sample by measurement of the H-alpha emission line. We find 3 ultra-fast
rotators (UFRs, vsini > 100km/s), and 8 stars with 30 < vsini < 100 km/s. The
UFRs have variable emission. Cross-correlation velocities measured for
ultra-fast rotators (UFRs) are shown to depend on rotation speed and the
filtering used. The radial velocity dispersion of the sample is 17 km/s. A new
double emission line spectroscopic binary with a period of 3.55 days has been
discovered, and another known one is in the sample. Three other objects are
suspected spectroscopic binaries, and at least six are visual doubles. The only
star in the sample observed to have significant lithium is a known TW Hya
Association member, TWA 8A. These results show that there are a number of young
(< 10^8 yr) and very young (< 10^7 yr) low mass stars in the immediate solar
neighbourhood. The H-alpha activity strength does not depend on rotation speed.
Our fast rotators are less luminous than similarly fast rotators in the
Pleiades. They are either younger than the Pleiades, or gained angular momentum
in a different way.Comment: 38 pages incl. 14 figures and 4 tables, plus 12 pages of table for
electronic journal only; LaTeX, aastex.cls. Accepted 07/18/02 for publication
in The Astronomical Journa
TGF-β Signaling Specifies Axons during Brain Development
In the mammalian brain, the specification of a single axon and multiple dendrites occurs early in the differentiation of most neuron types. Numerous intracellular signaling events for axon specification have been described in detail. However, the identity of the extracellular factor(s) that initiate neuronal polarity in vivo is unknown. Here, we report that transforming growth factor-β (TGF-β) initiates signaling pathways both in vivo and in vitro to fate naïve neurites into axons. Neocortical neurons lacking the type II TGF-β receptor (TβR2) fail to initiate axons during development. Exogenous TGF-β is sufficient to direct the rapid growth and differentiation of an axon, and genetic enhancement of receptor activity promotes the formation of multiple axons. Finally, we show that the bulk of these TGF-β-dependent events are mediated by site-specific phosphorylation of Par6. These results define an extrinsic cue for neuronal polarity in vivo that patterns neural circuits in the developing brain
Postsynaptic Positioning of Endocytic Zones and AMPA Receptor Cycling by Physical Coupling of Dynamin-3 to Homer
Endocytosis of AMPA receptors and other postsynaptic cargo occurs at endocytic zones (EZs), stably positioned sites of clathrin assembly adjacent to the postsynaptic density (PSD). The tight localization of postsynaptic endocytosis is thought to control spine composition and regulate synaptic transmission and plasticity. However, the molecular mechanisms that situate the EZ near the PSD, and the role of local spine endocytosis in synaptic transmission, are unknown. Here we report that a physical link between dynamin-3 and the postsynaptic adaptor Homer positions the EZ near the PSD. Disruption of dynamin-3 or its interaction with Homer uncouples the PSD from the EZ, resulting in synapses devoid of postsynaptic clathrin. This loss of the EZ leads to a loss of synaptic AMPA receptors and reduced excitatory synaptic transmission that corresponds with impaired synaptic recycling. Thus, a physical link between the PSD and the EZ ensures localized endocytosis and recycling by recapturing and maintaining a proximate pool of cycling AMPA receptors
Transsynaptic Signaling by Activity-Dependent Cleavage of Neuroligin-1
Adhesive contact between pre- and postsynaptic neurons initiates synapse formation during brain development and provides a natural means of trans-synaptic signaling. Numerous adhesion molecules and their role during synapse development have been described in detail. However, once established, the mechanisms of adhesive disassembly and its function in regulating synaptic transmission have been unclear. Here, we report that synaptic activity induces acute proteolytic cleavage of neuroligin-1 (NLG1), a postsynaptic adhesion molecule at glutamatergic synapses. NLG1 cleavage is triggered by NMDA receptor activation, requires Ca2+/calmodulin-dependent protein kinase, and is mediated by proteolytic activity of matrix metalloprotease 9 (MMP9). Cleavage of NLG1 occurs at single activated spines, is regulated by neural activity in vivo, and causes rapid destabilization of its presynaptic partner neurexin-1β (NRX1β). In turn, NLG1 cleavage depresses synaptic transmission by abruptly reducing presynaptic release probability. Thus, local proteolytic control of synaptic adhesion tunes synaptic transmission during brain development and plasticity
Genome Resources for ClimateâResilient Cowpea, an Essential Crop for Food Security
Cowpea (Vigna unguiculata L. Walp.) is a legume crop that is resilient to hot and droughtâprone climates, and a primary source of protein in subâSaharan Africa and other parts of the developing world. However, genome resources for cowpea have lagged behind most other major crops. Here we describe foundational genome resources and their application to the analysis of germplasm currently in use in West African breeding programs. Resources developed from the African cultivar IT97Kâ499â35 include a wholeâgenome shotgun (WGS) assembly, a bacterial artificial chromosome (BAC) physical map, and assembled sequences from 4355 BACs. These resources and WGS sequences of an additional 36 diverse cowpea accessions supported the development of a genotyping assay for 51 128 SNPs, which was then applied to five biâparental RIL populations to produce a consensus genetic map containing 37 372 SNPs. This genetic map enabled the anchoring of 100 Mb of WGS and 420 Mb of BAC sequences, an exploration of genetic diversity along each linkage group, and clarification of macrosynteny between cowpea and common bean. The SNP assay enabled a diversity analysis of materials from West African breeding programs. Two major subpopulations exist within those materials, one of which has significant parentage from South and East Africa and more diversity. There are genomic regions of high differentiation between subpopulations, one of which coincides with a cluster of nodulin genes. The new resources and knowledge help to define goals and accelerate the breeding of improved varieties to address food security issues related to limitedâinput smallâholder farming and climate stress
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