DOCSLIB.ORG

Multimodal Gradients Across Mouse Cortex

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Multimodal Gradients Across Mouse Cortex Multimodal gradients across mouse cortex Ben D. Fulchera,1, John D. Murrayb, Valerio Zerbic, and Xiao-Jing Wangd,e,1 aSchool of Physics, Sydney University, Sydney, NSW 2006, Australia; bDepartment of Psychiatry, Yale University School of Medicine, New Haven, CT 06511; cNeural Control of Movement Laboratory, Department of Health Sciences and Technology, Eidgenossische¨ Technische Hochschule Zurich,¨ 8057 Zurich,¨ Switzerland; dCenter for Neural Science, New York University, New York, NY 10003; and eShanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai 201210, China Edited by Robert Desimone, Massachusetts Institute of Technology, Cambridge, MA, and approved January 22, 2019 (received for review August 16, 2018) The primate cerebral cortex displays a hierarchy that extends from The ratio of T1-weighted to T2-weighted (T1w:T2w) images primary sensorimotor to association areas, supporting increas- is a noninvasive MRI measurement that has been measured in ingly integrated function underpinned by a gradient of hetero- mice, macaques, and humans, providing a common spatial refer- geneity in the brain’s microcircuits. The extent to which these ence map for linking large-scale cortical gradients across species. hierarchical gradients are unique to primate or may reflect a Commonly interpreted as a marker of intracortical myelin con- conserved mammalian principle of brain organization remains tent (45), T1w:T2w is also sensitive to a wide range of other unknown. Here we report the topographic similarity of large-scale microstructural properties (46). In macaque cortex, T1w:T2w gradients in cytoarchitecture, gene expression, interneuron cell is strongly correlated to the established structural hierarchy of densities, and long-range axonal connectivity, which vary from feedforward–feedback interareal laminar projections (47), and primary sensory to prefrontal areas of mouse cortex, highlighting in human cortex it follows dominant gene transcriptional gradi- an underappreciated spatial dimension of mouse cortical special- ents, positioning it as a strong candidate marker of hierarchical ization. Using the T1-weighted:T2-weighted (T1w:T2w) magnetic specialization (25). Here we show that gradients of diverse prop- resonance imaging map as a common spatial reference for com- erties of mouse cortex exhibit a common spatial patterning along parison across species, we report interspecies agreement in a a candidate functional hierarchy. We use T1w:T2w as a common range of large-scale cortical gradients, including a significant spatial reference to demonstrate a correspondence of gradients correspondence between gene transcriptional maps in mouse cor- of cytoarchitecture between mice, macaques, and humans and tex with their human orthologs in human cortex, as well as with transcriptional maps of ortholog genes between mice and notable interspecies differences. Our results support the view of humans. Our results reveal an interspecies conservation of cor- NEUROSCIENCE systematic structural variation across cortical areas as a core orga- tical gradients that may shape the functional specialization of nizational principle that may underlie hierarchical specialization mammalian cortical circuits, consistent with systematic structural in mammalian brains. variation across cortical areas as a core organizing principle (48). cortical hierarchy j gene expression j cortical gradients j Results interspecies comparison We analyzed the spatial maps of diverse cortical properties across 40 areas of the Allen Reference Atlas (ARA) (49), shown cross the brain, cortical microcircuits vary in their cytoarchi- in Fig. 1 A and B. The similarity between two spatial maps was Atecture (1–3); myeloarchitecture (3–5); dendritic and synap- quantified as the Spearman rank correlation coefficient, ρ, across tic structure (6–13); and the size, density, and laminar distribution as many cortical areas as could be matched between a given pair of distinct cell types (1, 3, 14–16). Many of these microstructural of modalities (40 unless otherwise specified). Corrected P val- properties vary across the cortex continuously as spatial gradients ues, Pcorr, are calculated using the method of Benjamini and (1–3, 17–20) that shape the specialized functional capabilities of Hochberg (50). different cortical areas (7), through variations in plasticity (5), inhibitory control (21), and electrophysiological properties (6, Significance 10). Prominent gradients follow a hierarchy of increasing func- tional integration, from primary sensory to transmodal associ- The brain is organized into processing streams, along which ation areas in primate cortex, pointing to their role in shaping incoming sensory information is processed at increasingly functional specialization along the cortical hierarchy (22–25). abstract and integrative levels. This specialization of function The mouse cortex is relatively uniform compared with the highly is thought to be underpinned by corresponding changes in the differentiated primate cortex (10, 26–28), but recent evidence has brain’s local circuitry. Here we combine a wide range of mea- nevertheless pointed to a global hierarchy of mouse cortical areas surements across the mouse brain, including the expression of (29, 30). It remains unknown whether the hierarchical gradients genes, cell densities, and axonal connectivity, to show that the of primate cortex exist and play a similar role in functional spe- properties of local circuits of the mouse brain vary along puta- cialization in the mouse and may therefore represent a conserved tive processing streams in a similar way to the primate brain. property of mammalian brain organization. This similarity across species points to common mechanisms The mouse is an ideal model to investigate gradients of cortical through which mammalian brains may process information. microstructure, with experimental datasets from diverse modal- ities available in standardized anatomical reference spaces (31). Author contributions: B.D.F., J.D.M., and X.-J.W. designed research; B.D.F. and V.Z. per- Cortical maps of a wide range of properties, many of which are formed research; J.D.M. and X.-J.W. contributed new reagents/analytic tools; B.D.F. and unavailable in humans, have been measured in mice, including (i) V.Z. analyzed data; and B.D.F., J.D.M., and X.-J.W. wrote the paper.y gene expression with approximate genome-wide coverage (32), The authors declare no conflict of interest.y (ii) interneuron cell densities (29), (iii) tract-traced axonal con- This article is a PNAS Direct Submission.y nectivity (30, 33–36), (iv) cytoarchitecture (37), (v) cell/neuron Published under the PNAS license.y density (38–40), and (vi) resting-state function magnetic reso- 1 To whom correspondence may be addressed. Email: [email protected] or nance imaging (fMRI) (41–43). Existing work has demonstrated [email protected] an association between pairs of these measurements (42–44), but This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. these data have not previously been characterized together from 1073/pnas.1814144116/-/DCSupplemental.y the viewpoint of macroscopic gradients. Published online February 19, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1814144116 PNAS j March 5, 2019 j vol. 116 j no. 10 j 4689–4695 Downloaded by guest on October 1, 2021 T1w:T2w A 1.18 RSPd B RSPagl VISamVISpm SSp-tr 1.1 SSp-ll PTLp VISp somatomotor 0.60 SSp-ul 1 medial SSp-bf VISal SSp-un VISl temporal ACAd visual AUDpo VISpl anterolateral PL MOs AUDd 0.9 MOp SSp-n FRP AUDp prefrontal SSp-m T1w:T2w 0.8 ORB SSs AUDv TEa 0.7 ECT Superior AId GU VISC PERI 0.6 Right Posterior PL AIv GU AIv AId ApI ILA TEa AIp SSs VISl Anterior ECT FRP MOs MOp VISp VISC Left PERI ORBl VISpl PTLp VISal RSPv ACAv AUDv RSPd ACAd AUDp SSp-ll AUDd SSp-n SSp-tr ORBvl ORBm VISpm SSp-ul VISam Inferior SSp-m AUDpo SSp-un RSPagl SSp-bfd Cortical area 10-3 0.7 7 40 ACAd AUDp SSp-bfd SSp-m SSp-n AIv C D E AId F TEa 4 MOp SSp-ul SSp-bf 35 MOs d 6 ACAv VISC SSp-m 0.6 VISpl VISp SSp-ll VISp SSs ORBvl SSp-un ORBl 30 SSp-tr VISal AUDpo VISam SSs RSPd 5 AUDv SSp-tr SSp-ll AUDd 0.5 AUDp AUDd ORBl VISpm 3 ACAv ACAd MOs PTLp 25 PL VISC SSp-ul FRP FRP SSp-n PTLp AId VISC 4 PL RSPagl VISpl MOs VISal FRP VISam ORBvl RSPv AId VISal 0.4 RSPagl ORBvl 20 VISl VISam GU AUDpo ILA ORBm VISpm 3 VISpl ORBl RSPd SSp-tr GU AIv AUDv VISpm 2 AIv AUDp 15 MOp TEa 0.3 ORBm TEa GU MOp VISl ORBm TEa SSp-bfd 2 VISC MOs VISal RSPv SSs Cytoarchitecture type AIp VISp 10 ORBvl AId ILA PERI RSPaglAUDv VISam VISpl SSp-m PL SSp-n PTLp Inferred hierarchical level ACAv AIp ORBl RSPv 0.2 ECT RSPd AUDd RSPd FRP ILA ACAv PERI VISpm AUDd AIp SSp-ul 1 AIp 1 SSp-ul SSs 5 PV:(PV+SST) cell density (L2/3) VISl SSp-m SSp-ll ORBm AIv ACAd ACAd SSp-bfd SSp-n ILA PLECT RSPagl Afferent axonal connection density RSPv SSp-tr VISp PERI 0.1 0 SSp-ll 0 AUDp 0.7 0.8 0.9 1.0 1.1 0.7 0.8 0.9 1.0 1.1 0.7 0.8 0.9 1.0 1.1 0.7 0.8 0.9 1.0 1.1 T1w:T2w T1w:T2w T1w:T2w T1w:T2w Fig. 1. The spatial map of the MRI measurement, T1w:T2w, is correlated with spatial maps of other structural properties. (A) Variation in T1w:T2w across mouse cortical areas (visualization through medial sections is in SI Appendix, Fig. S3). (B) T1w:T2w broadly decreases across families of connectivity-based groupings of cortical areas (30), from somatomotor areas to anterolateral and prefrontal areas. Groups are ordered by decreasing T1w:T2w, as are areas within each group. (C–F) Scatter plots are shown for T1w:T2w (horizontal axis) vs.
Load more

Recommended publications
  • Associations of Serotonin Receptor Gene HTR3A, HTR3B, and HTR3A Haplotypes with Bipolar Disorder in Chinese Patients
    Associations of serotonin receptor gene HTR3A, HTR3B, and HTR3A haplotypes with bipolar disorder in Chinese patients J. Jian1,2*, C. Li1,2*, J. Xu3, D. Qiao2, G. Mi2, X. Chen2 and M. Tang2 1Shandong University School of Medicine, Ji’nan, Shandong, China 2Shandong Mental Health Center Ji’nan, Shandong, China 3Business Management Department, Shandong Center for Disease Control and Prevention, Jinan, Shandong, China *These authors contributed equally to this study. Corresponding author: M. Tang E-mail: [email protected] Genet. Mol. Res. 15 (3): gmr.15038671 Received March 30, 2016 Accepted August 8, 2016 Published September 16, 2016 DOI http://dx.doi.org/10.4238/gmr.15038671 Copyright © 2016 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution ShareAlike (CC BY-SA) 4.0 License. ABSTRACT. Single nucleotide polymorphisms (SNPs) in HTR3A and HTR3B have been reported to be associated with bipolar disorder in European and Japanese populations. We explored the roles of 21 tag SNPs in HTR3A and HTR3B in susceptibility to bipolar disorder in a Chinese cohort. Twenty-one Tag SNPs were genotyped in a study consisting of 130 patients with bipolar disorder, who visited Shandong Mental Health Center between June 2013 and May 2014, and 109 healthy individuals as controls. All of the tag SNPs were genotyped using Sequenom MassArray matrix-assisted laser desorption/ionization time of flight spectrometry. Plink 1.07, Haploview 4.2, and SPSS 20.0 were used for the analysis of the genotypes and the associations of the haplotypes with bipolar disorder. Association analyses of tag Genetics and Molecular Research 15 (3): gmr.15038671 J.
    [Show full text]
  • Anti-GRIK1 / Glur5 Antibody (ARG59676)
    Product datasheet [email protected] ARG59676 Package: 50 μg anti-GRIK1 / GluR5 antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes GRIK1 / GluR5 Tested Reactivity Hu, Ms, Rat Tested Application IHC-P, WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name GRIK1 / GluR5 Species Human Immunogen Recombinant protein corresponding to R271-I450 of Human GRIK1. Conjugation Un-conjugated Alternate Names GluR5; GluK1; GLUR5; EEA3; GluR-5; Excitatory amino acid receptor 3; Glutamate receptor ionotropic, kainate 1; EAA3; Glutamate receptor 5; GLR5 Application Instructions Application table Application Dilution IHC-P 1:200 - 1:1000 WB 0.1 - 0.5 µg/ml Application Note IHC-P: Antigen Retrieval: Heat mediation was performed in Citrate buffer (pH 6.0) for 20 min. * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Properties Form Liquid Purification Affinity purification with immunogen. Buffer 0.9% NaCl, 0.2% Na2HPO4, 0.05% Sodium azide and 5% BSA. Preservative 0.05% Sodium azide Stabilizer 5% BSA Concentration 0.5 mg/ml Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C or below. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. Note For laboratory research only, not for drug, diagnostic or other use. www.arigobio.com 1/4 Bioinformation Gene Symbol GRIK1 Gene Full Name glutamate receptor, ionotropic, kainate 1 Background Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes.
    [Show full text]
  • A Guide to Glutamate Receptors
    A guide to glutamate receptors 1 Contents Glutamate receptors . 4 Ionotropic glutamate receptors . 4 - Structure ........................................................................................................... 4 - Function ............................................................................................................ 5 - AMPA receptors ................................................................................................. 6 - NMDA receptors ................................................................................................. 6 - Kainate receptors ............................................................................................... 6 Metabotropic glutamate receptors . 8 - Structure ........................................................................................................... 8 - Function ............................................................................................................ 9 - Group I: mGlu1 and mGlu5. .9 - Group II: mGlu2 and mGlu3 ................................................................................. 10 - Group III: mGlu4, mGlu6, mGlu7 and mGlu8 ............................................................ 10 Protocols and webinars . 11 - Protocols ......................................................................................................... 11 - Webinars ......................................................................................................... 12 References and further reading . 13 Excitatory synapse pathway
    [Show full text]
  • Chr21 Protein-Protein Interactions: Enrichment in Products Involved in Intellectual Disabilities, Autism and Late Onset Alzheimer Disease
    bioRxiv preprint doi: https://doi.org/10.1101/2019.12.11.872606; this version posted December 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Chr21 protein-protein interactions: enrichment in products involved in intellectual disabilities, autism and Late Onset Alzheimer Disease Julia Viard1,2*, Yann Loe-Mie1*, Rachel Daudin1, Malik Khelfaoui1, Christine Plancon2, Anne Boland2, Francisco Tejedor3, Richard L. Huganir4, Eunjoon Kim5, Makoto Kinoshita6, Guofa Liu7, Volker Haucke8, Thomas Moncion9, Eugene Yu10, Valérie Hindie9, Henri Bléhaut11, Clotilde Mircher12, Yann Herault13,14,15,16,17, Jean-François Deleuze2, Jean- Christophe Rain9, Michel Simonneau1, 18, 19, 20** and Aude-Marie Lepagnol- Bestel1** 1 Centre Psychiatrie & Neurosciences, INSERM U894, 75014 Paris, France 2 Laboratoire de génomique fonctionnelle, CNG, CEA, Evry 3 Instituto de Neurociencias CSIC-UMH, Universidad Miguel Hernandez-Campus de San Juan 03550 San Juan (Alicante), Spain 4 Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA 5 Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 34141, Republic of Korea 6 Department of Molecular Biology, Division of Biological Science, Nagoya University Graduate School of Science, Furo, Chikusa, Nagoya, Japan 7 Department of Biological Sciences, University of Toledo, Toledo, OH, 43606, USA 8 Leibniz Forschungsinstitut für Molekulare Pharmakologie
    [Show full text]
  • Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
    Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Identification of C3 As a Therapeutic Target for Diabetic Nephropathy By
    www.nature.com/scientificreports OPEN Identifcation of C3 as a therapeutic target for diabetic nephropathy by bioinformatics analysis ShuMei Tang, XiuFen Wang, TianCi Deng, HuiPeng Ge & XiangCheng Xiao* The pathogenesis of diabetic nephropathy is not completely understood, and the efects of existing treatments are not satisfactory. Various public platforms already contain extensive data for deeper bioinformatics analysis. From the GSE30529 dataset based on diabetic nephropathy tubular samples, we identifed 345 genes through diferential expression analysis and weighted gene coexpression correlation network analysis. GO annotations mainly included neutrophil activation, regulation of immune efector process, positive regulation of cytokine production and neutrophil-mediated immunity. KEGG pathways mostly included phagosome, complement and coagulation cascades, cell adhesion molecules and the AGE-RAGE signalling pathway in diabetic complications. Additional datasets were analysed to understand the mechanisms of diferential gene expression from an epigenetic perspective. Diferentially expressed miRNAs were obtained to construct a miRNA-mRNA network from the miRNA profles in the GSE57674 dataset. The miR-1237-3p/SH2B3, miR-1238-5p/ ZNF652 and miR-766-3p/TGFBI axes may be involved in diabetic nephropathy. The methylation levels of the 345 genes were also tested based on the gene methylation profles of the GSE121820 dataset. The top 20 hub genes in the PPI network were discerned using the CytoHubba tool. Correlation analysis with GFR showed that SYK, CXCL1, LYN, VWF, ANXA1, C3, HLA-E, RHOA, SERPING1, EGF and KNG1 may be involved in diabetic nephropathy. Eight small molecule compounds were identifed as potential therapeutic drugs using Connectivity Map. It is estimated that a total of 451 million people sufered from diabetes by 2017, and the number is speculated to be 693 million by 2045 1.
    [Show full text]
  • Kainate Receptors in Health and Disease
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Neuron Review Kainate Receptors in Health and Disease Juan Lerma1,* and Joana M. Marques1 1Instituto de Neurociencias, CSIC-UMH, San Juan de Alicante, 03550 Spain *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2013.09.045 Our understanding of the molecular properties of kainate receptors and their involvement in synaptic phys- iology has progressed significantly over the last 30 years. A plethora of studies indicate that kainate receptors are important mediators of the pre- and postsynaptic actions of glutamate, although the mechanisms under- lying such effects are still often a topic for discussion. Three clear fields related to their behavior have emerged: there are a number of interacting proteins that pace the properties of kainate receptors; their activity is unconventional since they can also signal through G proteins, behaving like metabotropic recep- tors; they seem to be linked to some devastating brain diseases. Despite the significant progress in their importance in brain function, kainate receptors remain somewhat puzzling. Here we examine discoveries linking these receptors to physiology and their probable implications in disease, in particular mood disorders, and propose some ideas to obtain a deeper understanding of these intriguing proteins. A Historical Overview The absence of specific antibodies against different KAR Most excitatory synapses in the brain use the amino acid gluta- subunits has been a significant limitation in terms of exploring re- mate as a neurotransmitter. Since the excitatory properties of ceptor distribution. Thus, most of the information regarding their glutamate were postulated nearly 40 years ago, an extraordinary tissue expression comes from in situ hybridization studies that, wealth of data has accumulated on the types of synaptic re- although informative, cannot reveal the subcellular distribution sponses triggered by this neurotransmitter.
    [Show full text]
  • Lysophosphatidic Acid Signaling in the Nervous System
    Neuron Review Lysophosphatidic Acid Signaling in the Nervous System Yun C. Yung,1,3 Nicole C. Stoddard,1,2,3 Hope Mirendil,1 and Jerold Chun1,* 1Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA 2Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, La Jolla, CA 92037, USA 3Co-first author *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2015.01.009 The brain is composed of many lipids with varied forms that serve not only as structural components but also as essential signaling molecules. Lysophosphatidic acid (LPA) is an important bioactive lipid species that is part of the lysophospholipid (LP) family. LPA is primarily derived from membrane phospholipids and signals through six cognate G protein-coupled receptors (GPCRs), LPA1-6. These receptors are expressed on most cell types within central and peripheral nervous tissues and have been functionally linked to many neural pro- cesses and pathways. This Review covers a current understanding of LPA signaling in the nervous system, with particular focus on the relevance of LPA to both physiological and diseased states. Introduction LPA synthesis/degradative enzymes (reviewed in Sigal et al., The human brain is composed of approximately 60%–70% lipids 2005; Brindley and Pilquil, 2009; Perrakis and Moolenaar, by dry weight (Svennerholm et al., 1994). These lipids can be 2014). In view of the broad neurobiological influences of LPA divided into two major pools, structural and signaling, which signaling, its dysregulation may lead to diverse neuropathologies include well-known families such as cholesterol, fatty acids, ei- (Bandoh et al., 2000; Houben and Moolenaar, 2011; Yung et al., cosanoids, endocannabinoids, and prostaglandins (Figure 1).
    [Show full text]
  • Resistance to Ondansetron: Role of Pharmacogenetics in Post-Operative Nausea and Vomiting
    The Egyptian Journal of Medical Human Genetics (2013) 14, 331–336 Ain Shams University The Egyptian Journal of Medical Human Genetics www.ejmhg.eg.net www.sciencedirect.com REVIEW Resistance to ondansetron: Role of pharmacogenetics in post-operative nausea and vomiting Kulsoom Farhat a,*, Muhammad Ismail b, Shabana Ali a, Anwar Kamal Pasha c a Army Medical College (National University of Sciences & Technology), Pakistan b Institute of Biomedical and Genetic Engineering, Pakistan c Combined Military Hospital, Rawalpindi, Pakistan Received 28 January 2013; accepted 17 March 2013 Available online 4 May 2013 KEYWORDS Abstract Post-operative nausea and vomiting is the most annoying and at the same time a danger- 5-Hydroxytryptamine type 3 ous side effect of general anaesthesia. Ondansetron is a routinely used anti emetic drug which is receptor antagonists; being administered by the trial and error principle. Though it did revolutionized the management Ondansetron; of this condition but by and large failed to completely eliminate the problem. Recently an important Post-operative nausea and factor possibly elucidating this failure is said to be the differing expression of genes controlling pro- vomiting; teins that are involved in transport and receptors related to this drug. Quite surprisingly these trans- Polymorphism; porter and receptor pathways have been found to be polymorphic and at the same time shown to be Pharmacogenetics related to efficacy of the drug. The differentiation between those responding to treatment and those not responding may pave a way to individualize treatment for emesis to a greater extent. This review highlights the pharmacogenetics related to this commonly used anti-emetic drug in anaesthesia.
    [Show full text]
  • Interplay Between Gating and Block of Ligand-Gated Ion Channels
    brain sciences Review Interplay between Gating and Block of Ligand-Gated Ion Channels Matthew B. Phillips 1,2, Aparna Nigam 1 and Jon W. Johnson 1,2,* 1 Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA; [email protected] (M.B.P.); [email protected] (A.N.) 2 Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA * Correspondence: [email protected]; Tel.: +1-(412)-624-4295 Received: 27 October 2020; Accepted: 26 November 2020; Published: 1 December 2020 Abstract: Drugs that inhibit ion channel function by binding in the channel and preventing current flow, known as channel blockers, can be used as powerful tools for analysis of channel properties. Channel blockers are used to probe both the sophisticated structure and basic biophysical properties of ion channels. Gating, the mechanism that controls the opening and closing of ion channels, can be profoundly influenced by channel blocking drugs. Channel block and gating are reciprocally connected; gating controls access of channel blockers to their binding sites, and channel-blocking drugs can have profound and diverse effects on the rates of gating transitions and on the stability of channel open and closed states. This review synthesizes knowledge of the inherent intertwining of block and gating of excitatory ligand-gated ion channels, with a focus on the utility of channel blockers as analytic probes of ionotropic glutamate receptor channel function. Keywords: ligand-gated ion channel; channel block; channel gating; nicotinic acetylcholine receptor; ionotropic glutamate receptor; AMPA receptor; kainate receptor; NMDA receptor 1. Introduction Neuronal information processing depends on the distribution and properties of the ion channels found in neuronal membranes.
    [Show full text]
  • Sex Differences in Glutamate Receptor Gene Expression in Major Depression and Suicide
    Molecular Psychiatry (2015) 20, 1057–1068 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp IMMEDIATE COMMUNICATION Sex differences in glutamate receptor gene expression in major depression and suicide AL Gray1, TM Hyde2,3, A Deep-Soboslay2, JE Kleinman2 and MS Sodhi1,4 Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F21,59 = 2.32, P = 0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups.
    [Show full text]