DOCSLIB.ORG

Alternative Splicing of AMPA Subunits in Prefrontal Cortical Fields Of

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Alternative Splicing of AMPA Subunits in Prefrontal Cortical Fields Of View metadata, citation and similar papers at core.ac.uk brought to you by CORE ORIGINAL RESEARCH ARTICLE published: 03 Januaryprovided 2012 by Frontiers - Publisher Connector PSYCHIATRY doi: 10.3389/fpsyt.2011.00072 Alternative splicing of AMPA subunits in prefrontal cortical fields of cynomolgus monkeys following chronic ethanol self-administration Glen Acosta1, David P.Freidman1, Kathleen A. Grant 2 and Scott E. Hemby 1,3* 1 Department of Physiology and Pharmacology, Wake Forest University, Winston-Salem, NC, USA 2 Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, USA 3 Department of Psychiatry and Behavioral Sciences, Wake Forest University, Winston-Salem, NC, USA Edited by: Functional impairment of the orbital and medial prefrontal cortex underlies deficits in exec- Lara Ray, University of California, USA utive control that characterize addictive disorders, including alcohol addiction. Previous Reviewed by: studies indicate that alcohol alters glutamate neurotransmission and one substrate of these Raj Sevak, University of California, USA effects may be through the reconfiguration of the subunits constituting ionotropic gluta- Shaolin Wang, University of Virginia, mate receptor (iGluR) complexes. Glutamatergic transmission is integral to cortico-cortical USA and cortico-subcortical communication and alcohol-induced changes in the abundance of *Correspondence: the receptor subunits and/or their splice variants may result in critical functional impair- Scott E. Hemby, Medical Center ments of prefrontal cortex in alcohol dependence. To this end, the effects of chronic Boulevard, Wake Forest University School of Medicine, Winston-Salem, ethanol self-administration on glutamate receptor ionotropic AMPA (GRIA) subunit vari- NC 27157, USA. ant and kainate (GRIK) subunit mRNA expression were studied in the orbitofrontal cortex e-mail: [email protected] (OFC), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC) of male cynomolgus monkeys. In DLPFC, total AMPA splice variant expression and total kainate receptor subunit expression were significantly decreased in alcohol drinking monkeys. Expression levels of GRIA3 flip and flop and GRIA4 flop mRNAs in this region were posi- tively correlated with daily ethanol intake and blood ethanol concentrations (BEC) averaged over the 6 months prior to necropsy. In OFC, AMPA subunit splice variant expression was reduced in the alcohol treated group. GRIA2 flop mRNA levels in this region were positively correlated with daily ethanol intake and BEC averaged over the 6 months prior to necropsy. Results from these studies provide further evidence of transcriptional regulation of iGluR subunits in the primate brain following chronic alcohol self-administration. Additional stud- ies examining the cellular localization of such effects in the framework of primate prefrontal cortical circuitry are warranted. Keywords: ethanol, AMPA, kainate, messenger RNA, prefrontal cortex, qPCR, primate INTRODUCTION self-reported alcohol-induced craving (Wrase et al., 2002; Myrick Alcohol abuse is characterized in part by short-term and long- et al.,2004). Furthermore,a priming dose of alcohol sensitizes cue- term biochemical alterations in brain regions that affect subse- induced responses in these regions (Bragulat et al., 2008). Such quent intake, withdrawal, relapse, and cognition. The majority of findings support the hypothesis that prefrontal cortical dysreg- research conducted in this area has focused on alterations in mid- ulation is involved in the mediation of craving and compulsive brain and forebrain regions within the mesolimbic dopamine sys- alcohol intake (Volkow and Fowler, 2000). tem that mediate hypothetical motivational processes (Di Chiara Despite evidence linking excessive alcohol intake to dysfunction and Imperato, 1988; Brodie et al., 1990). More recently, the of specific prefrontal cortical regions, studies exploring biochem- prefrontal cortex has received increasing attention in addiction ical correlates in prefrontal cortex have been limited to human processes because alcoholics show deficits in decision-making like post-mortem tissue analysis (Mitsuyama et al., 1998; Mayfield those of individuals with damage to specific prefrontal fields. et al., 2002; Alexander-Kaufman et al., 2006). The use of a non- In particular, damage to either the dorsolateral prefrontal cor- human primate model of ethanol self-administration enables a tex (DLPFC) or orbitofrontal cortex (OFC), produce impair- clinically relevant characterization of chronic alcohol intake in ments that suggest that these fields may be contributing substrates a well-controlled laboratory setting without confounding vari- in alcoholism (Bechara, 2003; Pears et al., 2003). Results from ables inherent in human post-mortem studies (e.g., reliable intake functional imaging studies support the idea of alcohol-induced measures, lifestyle characteristics, multidrug histories, etc.). The prefrontal cortical alterations. Functional magnetic resonance model exhibits important aspects of human alcohol consump- imaging (fMRI) has revealed increased activation of the medial tion, including an alcoholic drinking phenotype confirmed with frontal, orbitofrontal, and cingulate cortices that is correlated with blood ethanol concentrations (BEC; Grant et al., 2008). Moreover, www.frontiersin.org January 2012 | Volume 2 | Article 72 | 1 Acosta et al. Prefrontal AMPA/kainate expression and ethanol non-human primate cortex exhibits significant anatomical and neuroanatomical and biochemical milieu of the human brain. biochemical similarities with human cortex that facilitate the The primate cerebral cortex is highly elaborated in compari- translation of findings to humans (Preuss, 2001). Previous stud- son to rodents especially in prefrontal regions that are emerg- ies using this model have found marked alterations in GABA-A ing as important substrates for addictive disorders. In the rat, and NMDA receptor subunit mRNA expression in the DLPFC and the prefrontal cortex is composed only of a set of agranular OFC but not in anterior cingulate cortex (ACC; Hemby et al.,2006; fields (e.g., dorsal and ventral anterior cingulate, prelimbic and Acosta et al., 2010), suggesting region specific GABA/glutamate infralimbic fields) and lacks the intricate expansion found in imbalances in the primate prefrontal cortex. primates. The primate brain contains agranular fields as well α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid but adds dysgranular and granular fields that are not found in (AMPA) and kainate receptors comprise two additional families rodents (Carmichael and Price, 1994; Ongur and Price, 2000). of glutamate-gated ion channel receptors (Ozawa et al., 1998). The use of non-human primate models enables a clear and clin- AMPA and kainate receptors are critical for fast synaptic trans- ically relevant characterization of behavioral and biochemical mission and have important roles in neuronal development and changes associated with chronic alcohol use in a well-controlled long- and short-term neuroplasticity (Pinheiro and Mulle, 2006). laboratory setting. To further investigate the potential contribu- AMPA and kainate receptors are tetrameric assemblies of sub- tion of AMPA and kainate receptor subunit expression in the units composed of GluR1–4 and GluR5–7, KA1 and KA2 sub- prefrontal cortical dysfunction characteristic of alcoholism, we units, respectively (Keinanen et al., 1990; Rosenmund et al., 1998). examined AMPA and kainate receptor subunit mRNA expres- AMPA receptors are responsible for the majority of fast excitatory sion, including AMPA flip/flop variants in the DLPFC, OFC, synaptic transmission in the brain and their activation is neces- and ACC of cynomolgus monkeys following chronic ethanol sary for depolarization and release the tonic Mg2+ blockade of self-administration. NMDA receptors, thereby enabling NMDA receptor activation. AMPA receptor subunits undergo post-transcriptional process- EXPERIMENTAL PROCEDURES ing including alternative splicing to yield flip and flop variants SUBJECTS AND ETHANOL SELF-ADMINISTRATION that mediate receptor desensitization (Quirk et al., 2004), the rate Ten adult male cynomolgus monkeys (Macaca fascicularis; 5.5– of receptor re-sensitization (Partin et al., 1994) and of channel 6.5 years at beginning of experiment) were subjects for the present closing (Pei et al., 2007), thereby enabling greater diversity in experiments (n = 6 ethanol group, n = 4 control group). The channel kinetics and pharmacological profiles for these recep- drinking model and the animals behavior has been extensively tors. Kainate receptors are closely related to AMPA receptors analyzed elsewhere (Vivian et al., 2001; Grant et al., 2008). Six but constitute a separate family of ionotropic glutamate receptor adult male cynomolgus monkeys were quarantined for 2 months (iGluR) and have unique roles on synaptic transmission depend- and then transferred to the laboratory primate housing room and ing on receptor subunit composition and whether they are located assigned a cage within a quadrant rack as described previously. pre- or post-synaptically (Huettner, 2003; Plested and Mayer, Attached to one wall of each monkey’s home cage was an oper- 2007). ant panel that allowed access to all fluid and food requirements. The intoxicating and reinforcing effects of ethanol are mediated Monkeys were trained to operate the drinking panel in daily 60- in part by the effects on AMPA and kainate receptors (Valenzuela
Load more

Recommended publications
  • PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis
    PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis Jensen, Kathrine Louise; Sørensen, Gunnar; Dencker, Ditte; Owens, William Anthony; Rahbek-Clemmensen, Troels; Brett Lever, Michael; Runegaard, Annika H; Riis Christensen, Nikolaj; Weikop, Pia; Wörtwein, Gitta; Fink-Jensen, Anders; Madsen, Kenneth L; Daws, Lynette; Gether, Ulrik; Rickhag, Mattias Published in: eNeuro DOI: 10.1523/ENEURO.0422-17.2018 Publication date: 2018 Document version Publisher's PDF, also known as Version of record Document license: CC BY Citation for published version (APA): Jensen, K. L., Sørensen, G., Dencker, D., Owens, W. A., Rahbek-Clemmensen, T., Brett Lever, M., Runegaard, A. H., Riis Christensen, N., Weikop, P., Wörtwein, G., Fink-Jensen, A., Madsen, K. L., Daws, L., Gether, U., & Rickhag, M. (2018). PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis. eNeuro, 5(3). https://doi.org/10.1523/ENEURO.0422-17.2018 Download date: 25. sep.. 2021 New Research Disorders of the Nervous System PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis ء ء Kathrine Louise Jensen,1, Gunnar Sørensen,1,2, Ditte Dencker,2 William Anthony Owens,3 Troels Rahbek-Clemmensen,1 Michael Brett Lever,1 Annika H. Runegaard,1 Nikolaj Riis Christensen,1 Pia Weikop,2 Gitta Wörtwein,2 Anders Fink-Jensen,2 Kenneth L. Madsen,1 Lynette Daws,3 Ulrik Gether,1 and Mattias Rickhag1 DOI:http://dx.doi.org/10.1523/ENEURO.0422-17.2018 1Molecular Neuropharmacology and Genetics
    [Show full text]
  • AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder
    4814 • The Journal of Neuroscience, June 12, 2019 • 39(24):4814–4828 Neurobiology of Disease AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder Madhumita Yennawar,1 XRachel S. White,2 and XFrances E. Jensen2 1Department of Systems Pharmacology and Translational Therapeutics, and 2Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104 Pathogenic mutations in cyclin-dependent kinase-like 5 (CDKL5) result in CDKL5 deficiency disorder (CDD), a rare disease marked by early-life seizures, autistic behaviors, and intellectual disability. Although mouse models of CDD exhibit dendritic instability and alter- ations in synaptic scaffolding proteins, studies of glutamate receptor levels and function are limited. Here we used a novel mouse model of CDD, the Cdkl5R59X knock-in mouse (R59X), to investigate changes in synaptic glutamate receptor subunits and functional conse- quences. Male mice were used for all experiments to avoid the confounding effects of X-inactivation that would be present in female heterozygous mice. We showed that adult male R59X mice recapitulated the behavioral outcomes observed in other mouse models of CDD, including social deficits and memory and learning impairments, and exhibited decreased latency to seizure upon pentylenetetrazol administration. Furthermore, we observed a specific increase in GluA2-lacking ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors (AMPARs) in the adult R59X hippocampus, which is accompanied electrophysiologically by increased rectification ratio of AMPAR EPSCs and elevated early-phase long term potentiation (LTP). Finally, we showed that acute treatment with the GluA2-lacking AMPAR blocker IEM-1460 decreased AMPAR currents, and rescued social deficits, working memory impairments, and seizure behavior latency in R59X mice.
    [Show full text]
  • PICK1 Is Implicated in Organelle Motility in an Arp2/3 Complex–Independent Manner
    M BoC | ARTICLE PICK1 is implicated in organelle motility in an Arp2/3 complex–independent manner Yadaiah Madasua, Changsong Yangb, Malgorzata Boczkowskaa, Kelley A. Bethoneya, Adam Zwolaka, Grzegorz Rebowskia, Tatyana Svitkinab, and Roberto Domingueza aDepartment of Physiology, Perelman School of Medicine, and bDepartment of Biology, University of Pennsylvania, Philadelphia, PA 19104 ABSTRACT PICK1 is a modular scaffold implicated in synaptic receptor trafficking. It features Monitoring Editor a PDZ domain, a BAR domain, and an acidic C-terminal tail (ACT). Analysis by small- angle x- Thomas D. Pollard ray scattering suggests a structural model that places the receptor-binding site of the PDZ Yale University domain and membrane-binding surfaces of the BAR and PDZ domains adjacent to each other Received: Oct 14, 2014 on the concave side of the banana-shaped PICK1 dimer. In the model, the ACT of one subunit Revised: Dec 23, 2014 of the dimer interacts with the PDZ and BAR domains of the other subunit, possibly account- Accepted: Jan 26, 2015 ing for autoinhibition. Consistently, full-length PICK1 shows diffuse cytoplasmic localization, but it clusters on vesicle-like structures that colocalize with the trans-Golgi network marker TGN38 upon deletion of either the ACT or PDZ domain. This localization is driven by the BAR domain. Live-cell imaging further reveals that PICK1-associated vesicles undergo fast, nondi- rectional motility in an F-actin–dependent manner, but deleting the ACT dramatically reduces vesicle speed. Thus the ACT links PICK1-associated vesicles to a motility factor, likely myosin, but, contrary to previous reports, PICK1 neither binds nor inhibits Arp2/3 complex.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • The Glutamate Receptor Ion Channels
    0031-6997/99/5101-0007$03.00/0 PHARMACOLOGICAL REVIEWS Vol. 51, No. 1 Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. The Glutamate Receptor Ion Channels RAYMOND DINGLEDINE,1 KARIN BORGES, DEREK BOWIE, AND STEPHEN F. TRAYNELIS Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia This paper is available online at http://www.pharmrev.org I. Introduction ............................................................................. 8 II. Gene families ............................................................................ 9 III. Receptor structure ...................................................................... 10 A. Transmembrane topology ............................................................. 10 B. Subunit stoichiometry ................................................................ 10 C. Ligand-binding sites located in a hinged clamshell-like gorge............................. 13 IV. RNA modifications that promote molecular diversity ....................................... 15 A. Alternative splicing .................................................................. 15 B. Editing of AMPA and kainate receptors ................................................ 17 V. Post-translational modifications .......................................................... 18 A. Phosphorylation of AMPA and kainate receptors ........................................ 18 B. Serine/threonine phosphorylation of NMDA receptors ..................................
    [Show full text]
  • UNIVERSITY of CALIFORNIA, SAN DIEGO the Role of PICK1 And
    UNIVERSITY OF CALIFORNIA, SAN DIEGO The Role of PICK1 and PKC alpha in Alzheimer’s Disease A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Neurosciences by Stephanie Isabel Alfonso Committee in charge: Professor Roberto Malinow, Chair Professor Andrea Chiba Professor Todd Coleman Professor Fred Gage Professor Gentry Patrick 2016 The Dissertation of Stephanie Isabel Alfonso is approved, and it is acceptable in quality and form for publication on microfilm and electronically: Chair University of California, San Diego 2016 iii DEDICATION I would like to dedicate this thesis to my son and inspiration, Alex Alfonso. Thank you for changing my life and giving me a purpose to live. It is your love and your smile that keep me going everyday and I could never imagine a life without you. This will be the beginning of a major turning point in our lives and I’m glad you’ll be there to share it with me. Tambien le dedico esta tésis a mis padres y mi hermano que siempre han estado alli para ayudarme con todo. Siempre han sido un gran apoyo y nunca les podre pagar lo que han hecho por mi. Gracias por todo el amor que me han dado a mi y a mi hijo. Los quiero mas a que a nadie en el mundo, Steph. iv TABLE OF CONTENTS Signature Page…………………………………………………………………… iii Dedication………………………………………………………………………... iv Table of Contents……………………………………………………………….... v List of Figures.…………………............................................................................ vi Acknowledgements………………………………………………………………. vii Vita………………………………………..…………………………………..….. viii Abstract of the Dissertation ……………………………………………………… ix Introduction………………………………………………………………………. 1 Chapter I- Synapto-depressive effects of Aβ require PICK1 …………………......3 Chapter II- PKCα’s role in Alzheimer’s Disease …………..……………………..20 Appendix………………………………………………………………………….
    [Show full text]
  • PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis
    New Research Disorders of the Nervous System PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis ء ء Kathrine Louise Jensen,1, Gunnar Sørensen,1,2, Ditte Dencker,2 William Anthony Owens,3 Troels Rahbek-Clemmensen,1 Michael Brett Lever,1 Annika H. Runegaard,1 Nikolaj Riis Christensen,1 Pia Weikop,2 Gitta Wörtwein,2 Anders Fink-Jensen,2 Kenneth L. Madsen,1 Lynette Daws,3 Ulrik Gether,1 and Mattias Rickhag1 DOI:http://dx.doi.org/10.1523/ENEURO.0422-17.2018 1Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark, 2Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark, and 3Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, TX 78229 Abstract Protein interacting with C-kinase 1 (PICK1) is a widely expressed scaffold protein known to interact via its PSD-95/discs-large/ZO-1 (PDZ)-domain with several membrane proteins including the dopamine (DA) transporter (DAT), the primary target for cocaine’s reinforcing actions. Here, we establish the importance of PICK1 for behavioral effects observed after both acute and repeated administration of cocaine. In PICK1 knock-out (KO) mice, the acute locomotor response to a single injection of cocaine was markedly attenuated. Moreover, in support of a role for PICK1 in neuroadaptive changes induced by cocaine, we observed diminished cocaine intake in a self-administration paradigm. Reduced behavioral effects of cocaine were not associated with decreased striatal DAT distribution and most likely not caused by the ϳ30% reduction in synaptosomal DA uptake observed in PICK1 KO mice.
    [Show full text]
  • Deletion of Glutamate Receptor Trafficking Proteins in the Medial Prefrontal Cortex and Their Sex-Specific Effects on Cocaine Addiction
    DELETION OF GLUTAMATE RECEPTOR TRAFFICKING PROTEINS IN THE MEDIAL PREFRONTAL CORTEX AND THEIR SEX-SPECIFIC EFFECTS ON COCAINE ADDICTION A Dissertation Submitted to the Temple University Graduate Board In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY by Megan Marie Wickens May 2020 Examining Committee Members: Dr. Lisa Briand, Advisory Chair, Temple University Psychology Department Dr. Debra Bangasser, Temple University Psychology Department Dr. Vinay Parikh, Temple University Psychology Department Dr. Mathieu Wimmer, Temple University Psychology Department Dr. Vishnu Murty, Temple University Psychology Department Dr. Scott Rawls, Temple University Pharmacology Department ABSTRACT Dysregulation of glutamatergic signaling mechanisms is a component of many psychiatric diseases. A number of these diseases exhibit a bias toward one sex, yet the ways in which glutamate is affected by or modulates this bias is poorly understood. In cocaine addiction, women progress from initial use of the drug to substance use disorder faster than men, and have more difficulty remaining abstinent. The same is true in female rodents. We used a mouse model of cocaine self-administration to study the role of glutamate receptor trafficking proteins in cocaine addiction-like behavior in males and females. In the first set of experiments, mice received a conditional knockout of glutamate receptor interacting protein 1 (GRIP1) in the medial prefrontal cortex (mPFC). This led to an increase in motivation for cocaine as well as enhanced likelihood of relapse behavior, as measured by a progressive ratio schedule and cue-induced reinstatement, respectively. No sex differences were seen after prefrontal deletion of GRIP1. The next set of experiments used the same behavioral paradigm, but mice received a conditional knockout of protein interacting with C kinase 1 (PICK1) in the mPFC.
    [Show full text]
  • Ampa Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of Cdkl5 Deficiency Disorder
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2018 Ampa Receptor Dysregulation And Therapeutic Interventions In A Mouse Model Of Cdkl5 Deficiency Disorder Madhumita Yennawar University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Neuroscience and Neurobiology Commons Recommended Citation Yennawar, Madhumita, "Ampa Receptor Dysregulation And Therapeutic Interventions In A Mouse Model Of Cdkl5 Deficiency Disorder" (2018). Publicly Accessible Penn Dissertations. 3209. https://repository.upenn.edu/edissertations/3209 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/3209 For more information, please contact [email protected]. Ampa Receptor Dysregulation And Therapeutic Interventions In A Mouse Model Of Cdkl5 Deficiency Disorder Abstract CDKL5 Deficiency Disorder (CDD) is a rare disease that presents as a set of neurological deficits including early-life epilepsy, intellectual disability, and autistic-like behaviors. It results from pathogenic mutations in the gene for cyclin-dependent kinase-like 5 (CDKL5), a protein that is highly expressed in brain. There is no cure for CDD and seizures in this disorder are typically resistant to traditional anti-epileptic drugs, although some patients respond well to cannabidiol. However, underlying mechanisms of what causes hyperexcitability and neurological deficits in CDD is poorly understood. We investigated the novel Cdkl5R59X mouse (R59X), and observed that mutant mice have social interaction and memory deficits, and decreased latency to seizure after administration of pentylenetetrazol. Given the observed behavioral alterations and hyperexcitability in R59X mice, we hypothesized that mutant mice would exhibit underlying molecular and functional alterations in proteins involved in regulating the E:I balance.
    [Show full text]
  • Trafficking of Kainate Receptors
    Membranes 2014, 4, 565-595; doi:10.3390/membranes4030565 OPEN ACCESS membranes ISSN 2077-0375 www.mdpi.com/journal/membranes Review Trafficking of Kainate Receptors Steffen Pahl 1;2;3, Daniel Tapken 1, Simon C. Haering 1;3;4 and Michael Hollmann 1;2;* 1 Department of Biochemistry I, Ruhr University Bochum, Universitätsstr. 150, 44780 Bochum, Germany; E-Mails: [email protected] (S.P.); [email protected] (D.T.); [email protected] (S.C.H.) 2 International Graduate School of Neuroscience, Ruhr University Bochum, Universitätsstr. 150, 44780 Bochum, Germany 3 Ruhr University Research School, Ruhr University Bochum, Universitätsstr. 150, 44780 Bochum, Germany 4 Graduate School of Chemistry and Biochemistry, Ruhr University Bochum, Universitätsstr. 150, 44780 Bochum, Germany * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +49-234-32-28225; Fax: +49-234-32-14244. Received: 6 July 2014; in revised form: 4 August 2014 / Accepted: 12 August 2014 / Published: 20 August 2014 Abstract: Ionotropic glutamate receptors (iGluRs) mediate the vast majority of excitatory neurotransmission in the central nervous system of vertebrates. In the protein family of iGluRs, kainate receptors (KARs) comprise the probably least well understood receptor class. Although KARs act as key players in the regulation of synaptic network activity, many properties and functions of these proteins remain elusive until now. Especially the precise pre-, extra-, and postsynaptic localization of KARs plays a critical role for neuronal function, as an unbalanced localization of KARs would ultimately lead to dysregulated neuronal excitability. Recently, important advances in the understanding of the regulation of surface expression, function, and agonist-dependent endocytosis of KARs have been achieved.
    [Show full text]
  • SUSD4 Controls Activity-Dependent Degradation of AMPA Receptor GLUA2 and Synaptic Plasticity
    bioRxiv preprint doi: https://doi.org/10.1101/859587; this version posted November 29, 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. SUSD4 Controls Activity-Dependent Degradation of AMPA Receptor GLUA2 and Synaptic Plasticity I. González-Calvo1,2,†, K. Iyer1,†, M. Carquin1, A. Khayachi1, F.A. Giuliani2, J. Vincent3, M. Séveno4, S.M. Sigoillot1, M. Veleanu1, S. Tahraoui1, M. Albert1, O. Vigy5, Y. Nadjar6, A. Dumoulin6, A. Triller6, J.-L. Bessereau7, L. Rondi-Reig3, P. Isope2, F. Selimi1* Affiliations: 1 Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS, INSERM, PSL Research University, Paris, France. 2 Institut de Neurosciences Cellulaires et Intégratives (INCI), CNRS, Université de Strasbourg, , Strasbourg, France. 3 Institut Biology Paris Seine (IBPS), Neuroscience Paris Seine (NPS), CeZaMe, CNRS, Sorbonne University, INSERM, Paris, France. 4 BioCampus Montpellier, CNRS, INSERM, Université de Montpellier, Montpellier, France. 5 Institut de Génomique Fonctionnelle, CNRS, INSERM, Université de Montpellier, Montpellier, France. 6 École Normale Supérieure, Institut de Biologie de l'ENS, INSERM, CNRS, PSL Research University, Paris, France. 7 Université de Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut Neuromyogène, 69008, Lyon, France. * Correspondence to: [email protected] † Equal contribution. Summary At excitatory synapses, the choice between recycling or degradation of glutamate AMPA receptors controls the direction of synaptic plasticity. In this context, how the degradation machinery is targeted to specific synaptic substrates in an activity-dependent manner is not understood. Here we show that SUSD4, a complement-related transmembrane protein, is a tether for HECT ubiquitin ligases of the NEDD4 subfamily, which promote the degradation of a large number of cellular substrates.
    [Show full text]
  • Role of Satb1 and Satb2 Transcription Factors in the Glutamate Receptors Expression and Ca2+ Signaling in the Cortical Neurons in Vitro
    International Journal of Molecular Sciences Article Role of Satb1 and Satb2 Transcription Factors in the Glutamate Receptors Expression and Ca2+ Signaling in the Cortical Neurons In Vitro Egor A. Turovsky 1,2,* , Maria V. Turovskaya 1, Evgeniya I. Fedotova 1, Alexey A. Babaev 2, Victor S. Tarabykin 2,3 and Elena G. Varlamova 1,* 1 Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Institute of Cell Biophysics of the Russian Academy of Sciences, 142290 Pushchino, Russia; [email protected] (M.V.T.); [email protected] (E.I.F.) 2 Institute of Neuroscience, Lobachevsky State University of Nizhniy Novgorod, 23 Prospekt Gagarina, 603950 Nizhny Novgorod, Russia; [email protected] (A.A.B.); [email protected] (V.S.T.) 3 Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Charitéplatz 1, 10117 Berlin, Germany * Correspondence: [email protected] or [email protected] (E.A.T.); [email protected] or [email protected] (E.G.V.) Abstract: Transcription factors Satb1 and Satb2 are involved in the processes of cortex development and maturation of neurons. Alterations in the expression of their target genes can lead to neurode- generative processes. Molecular and cellular mechanisms of regulation of neurotransmission by these transcription factors remain poorly understood. In this study, we have shown that transcription Citation: Turovsky, E.A.; Turovskaya, factors Satb1 and Satb2 participate in the regulation of genes encoding the NMDA-, AMPA-, and M.V.; Fedotova, E.I.; Babaev, A.A.; KA- receptor subunits and the inhibitory GABA(A) receptor. Deletion of gene for either Satb1 or Tarabykin, V.S.; Varlamova, E.G.
    [Show full text]