Synaptically driven endocannabinoid release requires Ca2+- assisted metabotropic glutamate receptor subtype 1 to phospholipase C β4 signaling cascade in the cerebellum

金沢大学医薬保健研究域保健学系Endocannabinoids mediate retrograde signaling and modulate synaptic transmission in various regions of the CNS. Depolarization-induced elevation of intracellular Ca2+ concentration causes endocannabinoid-mediated suppression of excitatory/inhibitory synaptic transmission. Activation of G q/11-coupled receptors including group I metabotropic glutamate receptors (mGluRs) also causes endocannabinoid-mediated suppression of synaptic transmission. However, precise mechanisms of endocannabinoid production initiated by physiologically relevant synaptic activity remain to be determined. To address this problem, we made whole-cell recordings from Purkinje cells (PCs) in mouse cerebellar slices and examined their excitatory synapses arising from climbing fibers (CFs) and parallel fibers (PFs). We first characterized three distinct modes to induce endocannabinoid release by analyzing CF to PC synapses. The first mode is strong activation of mGluR subtype 1 (mGluR1)-phospholipase C (PLC) β4 cascade without detectable Ca 2+ elevation. The second mode is Ca2+ elevation to a micromolar range without activation of the mGluR1-PLC/34 cascade. The third mode is the Ca2+-assisted mGluR1-PLCβ4 cascade that requires weak mGluR1 activation and Ca2+ elevation to a submicromolar range. By analyzing PF to PC synapses, we show that the third mode is essential for effective endocannabinoid release from PCs by excitatory synaptic activity. Furthermore, our biochemical analysis demonstrates that combined weak mGluR1 activation and mild depolarization in PCs effectively produces 2-arachidonoylglycerol (2-AG), a candidate of endocannabinoid, whereas either stimulus alone did not produce detectable 2-AG. Our results strongly suggest that under physiological conditions, excitatory synaptic inputs to PCs activate the Ca2+-assisted mGluR1-PLCβ4 cascade, and thereby produce 2-AG, which retrogradely modulates synaptic transmission to PCs. Copyright © 2005 Society for Neuroscience.This work was supported by Grants-in-Aid for Scientific Research and Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Sports, Culture, Science and Technology ofJapan. This work was alsosupported by theJapan Society for the Promotion of Science (JSPS) and the Toyota RIKEN Foundation. T.M. was a recipient of JSPS Research Fellowships for Young Scientists and the Research Aid of Inoue Foundation for Science. We thank S. Arai for 2-AG estimation and Drs. K. Hashimoto and T. Tabata for comments on this work

A Report on Overseas Teaching Practicum by Graduate Students in Elementary/Secondary Schools in the United States (Ⅶ)

The present reports is on the 7th overseas teaching practicum in the United States by 15 graduate students of Hiroshima University, Japan, partly organized by Hiroshima University Global Partnership School Center since 2007. The group was comprised of 13 elementary school and 2 secondary school education major graduate students. They planned and conducted lessons in English in three local public schools in North Carolina. The expected outcomes of this project were: 1) to self-develop practical instructional competence by teaching pupils with diverse backgrounds in the U.S.; 2) to enhance the abilities in developing teaching materials through hands-on teaching experiences in English; and 3) to acquire the abilities to design, implement and evaluate programs for promoting global partnership. In addition, the teaching experience was followed by cross-cultural study visits to Raleigh, NC and Washington, D.C. It helped to boost our group motivation that the local media, newspaper and TV, and the city Board of Education covered our visit. It is hoped that this project will enhance the students’ teaching competence in designing quality materials/lessons and classroom communication skills in English

The Role of Emotional Abuse in Intimate Partner Violence and Health Among Women in Yokohama, Japan

Objectives. As part of the World Health Organization's cross-national research effort, we investigated the relationship between various health indicators and the experience of intimate partner violence (IPV), which included emotional, physical, and sexual abuse, among women in Yokohama, Japan

MHC class I-dressing is mediated via phosphatidylserine recognition and is enhanced by polyI:C

Summary: In addition to cross-presentation, cross-dressing plays an important role in the induction of CD8+ T cell immunity. In the process of cross-dressing, conventional dendritic cells (DCs) acquire major histocompatibility complex class I (MHCI) from other cells and subsequently prime CD8+ T cells via the pre-formed antigen-MHCI complexes without antigen processing. However, the mechanisms underlying the cross-dressing pathway, as well as the relative contributions of cross-presentation and cross-dressing to CD8+ T cell priming are not fully understood. Here, we demonstrate that DCs rapidly acquire MHCI-containing membrane fragments from dead cells via the phosphatidylserine recognition-dependent mechanism for cross-dressing. The MHCI dressing is enhanced by a TLR3 ligand polyinosinic-polycytidylic acid (polyI:C). Further, polyI:C promotes not only cross-presentation but also cross-dressing in vivo. Taken together, these results suggest that cross-dressing as well as cross-presentation is involved in inflammatory diseases associated with cell death and type I IFN production

An Evaluation Trial of The National Perfusion Registry

The International Consortium for Evidence-Based Perfusion (ICEBP) is a collaborative group whose mission is to improve, continuously, the delivery of care and outcomes for patients undergoing cardiac surgery. To achieve this end, the ICEBP supports the development of perfusion registries to evaluate clinical practices and has established evidence-based guidelines for perfusion. The Japanese Society of Extra-Corporeal Technology in Medicine (JaSECT) developed a perfusion registry to examine variation in perfusion practice in Japan. A pilot study was designed to determine the rate and accuracy of data extraction from patients’ medical records and perfusion practice records and the subsequent entry of data into the registry form. We designed an input matching test using medical records and perfusion records from a sample of patients. Five institutions participated in data extraction and entry from 10 randomly selected case records. Perfusionists entered data in the registry form in accordance with the instruction manual prepared by the JaSECT guideline committee. The time taken to input every case in the registry was measured. An interview-based survey was carried out across institutions after the completion of the pilot. The time required for data entry stabilized after approximately five cases to a rate that was 40% of the first case entry time. Data entered into the registry by perfusionists for multiple-choice items were accurate 65% of the time and accurate 25% of the time for numerical data. The interview-based survey identified a total of 38 opportunities for improvement in the input form and 58 recommended changes for the instruction manual. The accuracy of data may be improved by developing a method allowing the objective detection of deficient data when present in the perfusion case record by developing automatic data acquisition from the automatic perfusion recording system currently in use, and by changing as many numerical value input items as possible to multiple-choice items

Suppression of amyloid-β secretion from neurons by cis-9, trans-11-octadecadienoic acid, an isomer of conjugated linoleic acid

Two common conjugated linoleic acids (LAs), cis-9, trans-11 CLA (c9,t11 CLA) and trans-10, cis-12 CLA (t10,c12 CLA), exert various biological activities. However, the effect of CLA on the generation of neurotoxic amyloid-beta (A beta) protein remains unclear. We found that c9,t11 CLA significantly suppressed the generation of A beta in mouse neurons. CLA treatment did not affect the level of beta-site APP-cleaving enzyme 1 (BACE1), a component of active gamma-secretase complex presenilin 1 amino-terminal fragment, or A beta protein precursor (APP) in cultured neurons. BACE1 and gamma-secretase activities were not directly affected by c9,t11 CLA. Localization of BACE1 and APP in early endosomes increased in neurons treated with c9,t11 CLA; concomitantly, the localization of both proteins was reduced in late endosomes, the predominant site of APP cleavage by BACE1. The level of CLA-containing phosphatidylcholine (CLA-PC) increased dramatically in neurons incubated with CLA. Incorporation of phospholipids containing c9,t11 CLA, but not t10,c12 CLA, into the membrane may affect the localization of some membrane-associated proteins in intracellular membrane compartments. Thus, in neurons treated with c9,t11 CLA, reduced colocalization of APP with BACE1 in late endosomes may decrease APP cleavage by BACE1 and subsequent A beta generation. Our findings suggest that the accumulation of c9,t11 CLA-PC/LPC in neuronal membranes suppresses the production of neurotoxic A beta in neurons

Deficient neural activity subserving decision-making during reward waiting time in intertemporal choice in adult attention-deficit hyperactivity disorder.

Impulsivity, which significantly affects social adaptation, is an important target behavioral characteristic in interventions for attention-deficit hyperactivity disorder (ADHD). Typically, people are willing to wait longer to acquire greater rewards. Impulsivity in ADHD may be associated with brain dysfunction in decision-making involving waiting behavior under such situations. We tested the hypothesis that brain circuitry during a period of waiting (i.e., prior to the acquisition of reward) is altered in adults with ADHD

Preliminary evidence of altered neural response during intertemporal choice of losses in adult attention-deficit hyperactivity disorder.

Impulsive behaviours are common symptoms of attention-deficit hyperactivity disorder (ADHD). Although previous studies have suggested functional models of impulsive behaviour, a full explanation of impulsivity in ADHD remains elusive. To investigate the detailed mechanisms behind impulsive behaviour in ADHD, we applied an economic intertemporal choice task involving gains and losses to adults with ADHD and healthy controls and measured brain activity by functional magnetic resonance imaging. In the intertemporal choice of future gains, we observed no behavioural or neural difference between the two groups. In the intertemporal choice of future losses, adults with ADHD exhibited higher discount rates than the control participants. Furthermore, a comparison of brain activity representing the sensitivity of future loss in the two groups revealed significantly lower activity in the striatum and higher activity in the amygdala in adults with ADHD than in controls. Our preliminary findings suggest that an altered size sensitivity to future loss is involved in apparent impulsive choice behaviour in adults with ADHD and shed light on the multifaceted impulsivity underlying ADHD