DOCSLIB.ORG

Abl2:Cortactin Interactions Regulate Dendritic Spine Stability Via Control of a Stable Filamentous Actin Pool

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Abl2:Cortactin Interactions Regulate Dendritic Spine Stability Via Control of a Stable Filamentous Actin Pool Research Articles: Cellular/Molecular Abl2:cortactin interactions regulate dendritic spine stability via control of a stable filamentous actin pool https://doi.org/10.1523/JNEUROSCI.2472-20.2021 Cite as: J. Neurosci 2021; 10.1523/JNEUROSCI.2472-20.2021 Received: 21 September 2020 Revised: 15 January 2021 Accepted: 16 February 2021 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2021 the authors 1 Abl2:cortactin interactions regulate dendritic spine stability via control of a stable 2 filamentous actin pool. 3 4 Abbreviated title: Abl2 and cortactin regulate spine actin stability. a,d* a,b,c,* 5 Juliana E. Shawa, Michaela B. C. Kilanderd, Yu-Chih Lin and Anthony J. Koleske a b c 6 Departments of Molecular Biophysics and Biochemistry, Neuroscience, Interdepartmental 7 Neuroscience Program, Yale University, New Haven, CT 06520, U.S.A. 8 dProgram in Neuroscience, Hussman Institute for Autism, Baltimore, MD 21201, U.S.A. * 9 Co-corresponding authors: [email protected] and [email protected] 10 Number of Pages: 41 11 Number of Figures: 7 12 Number of Tables: 1 13 Number of multimedia: 0 14 Number 3D models: 0 15 Number of words for abstract: 220 words 16 Number of words for introduction: 652 words 17 Number of words for discussion: 1,655 words 18 19 Conflict of interest statement: The authors declare no competing financial interests. 20 21 Acknowledgements: We thank Aaron Levy, Josie Bircher, Melissa Carrizales and Amanda 22 Jeng for helpful comments on this manuscript, as well as other members of the Koleske lab for 23 their critical discussion and suggestions. This work was supported by NIH grants NS089662 24 (A.J.K.), NS105640 (A.J.K. and Michael J. Higley), MH115939 (A.J.K.), F31 MH116571 (J.E.S.), 25 and J.E.S. was supported on NIH training grant T32GM007223 (Susan J. Baserga). 26 1 27 Abstract 28 Dendritic spines act as the receptive contacts at most excitatory synapses. Spines are enriched 29 in a network of actin filaments comprised of two kinetically distinct pools. The majority of spine 30 actin is highly dynamic and regulates spine size, structural plasticity, and postsynaptic density 31 organization. The remainder of the spine actin network is more stable, but the function of this 32 minor actin population is not well understood, as tools to study it have not been available. 33 Previous work has shown that disruption of the Abl2/Arg nonreceptor tyrosine kinase in mice 34 compromises spine stability and size. Here, using cultured hippocampal neurons pooled from 35 both sexes of mice, we provide evidence that binding to cortactin tethers Abl2 in spines, where 36 Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability. 37 Using fluorescence recovery after photobleaching of GFP-actin, we find that disruption of 38 Abl2:cortactin interactions eliminates stable actin filaments in dendritic spines, significantly 39 reducing spine density. A subset of spines remaining after Abl2 depletion retain their stable 40 actin pool and undergo activity-dependent spine enlargement, associated with increased 41 cortactin and GluN2B levels. Finally, tonic increases in synaptic activity rescue spine loss upon 42 Abl2 depletion by promoting cortactin enrichment in vulnerable spines. Together, our findings 43 strongly suggest Abl2:cortactin interactions promote spine stability by maintaining pools of 44 stable actin filaments in spines. 45 46 Significance Statement 47 Dendritic spines contain two kinetically distinct pools of actin. The more abundant, highly 48 dynamic pool regulates spine shape, size, and plasticity. The function of the smaller, stable 49 actin network is not well understood, as tools to study it have not been available. We 50 demonstrate here that Abl2 and its substrate and interaction partner, cortactin, are essential to 51 maintain the stable pool in spines. Depletion of the stable actin pool via disruption of Abl2 or 52 cortactin, or interactions between the proteins, significantly reduces spine stability. We also 2 53 provide evidence that tonic increases in synaptic activity promote spine stability via enrichment 54 of cortactin in spines, suggesting synaptic activity acts on the stable actin pool to stabilize 55 dendritic spines. 3 56 Introduction 57 Dendritic spines serve as receptive post-synaptic compartments on excitatory neurons 58 and defects in their formation, density and shape are hallmarks of many brain disorders (Fiala et 59 al., 2002; Penzes et al., 2011). Spine shape and stability are principally supported by a 60 filamentous actin network, which also organizes scaffolding proteins and neurotransmitter 61 receptors at the post- synaptic density (Fischer et al., 1998; Alvarez and Sabatini, 2007; 62 Schubert and Dotti, 2007; Lin and Webb, 2009; Hotulainen and Hoogenraad, 2010). Spine actin 63 filaments assemble into higher-order structures that undergo dynamic rearrangements and 64 provide the forces to drive changes in spine shape and size (Matus, 2000; Luo, 2002; Sekino et 65 al., 2007; Chazeau and Giannone, 2016). Indeed, molecules that regulate spine plasticity and 66 stability, including cell surface receptors and kinases, often converge on signaling pathways that 67 control polymerization, stability, and contractility of actin networks. Therefore, the cytoskeletal 68 machinery is a key module to regulate spine plasticity and stability. 69 Fluorescence recovery after photobleaching (FRAP) experiments of GFP-actin have 70 determined that most (80-85%) spine actin filaments are dynamic, undergoing ongoing 71 polymerization and turnover within 10s of seconds, while the remainder of actin is more stable. 72 These distinct kinetic pools of actin likely play unique roles in the spine. Dynamic filaments 73 mediate a net retrograde flow of actin from the spine periphery toward the spine core and are 74 perfectly positioned to promote changes in spine size and shape (Honkura et al., 2008; Frost et 75 al., 2010) and also regulate neurotransmitter receptor localization or gating properties 76 (Rosenmund and Westbrook, 1993; Borgdorff and Choquet, 2002; Kerr and Blanpied, 2012). 77 Photoactivation of mEOS3.2-actin reveals that the small, stable pool of actin is enriched at the 78 spine base and turns over much more slowly (t ~17 minutes)(Honkura et al., 2008). The relative 79 proportion of stable actin increases during synapse maturation (Koskinen et al., 2014) and may 80 serve as a base for polymerization of new actin during spine enlargement (Mikhaylova et al., 4 81 2018). The functions of the stable actin pool have been largely understudied, primarily because 82 we lack an in-depth understanding of the molecules and mechanisms that regulate it. 83 The Abl2/Arg nonreceptor tyrosine kinase interacts with its substrate and binding partner 84 cortactin to regulate actin-based structures in many cellular contexts (MacGrath and Koleske, 85 2012a; Schnoor et al., 2018). Both proteins localize to dendritic spines where they promote 86 spine stability (Hering and Sheng, 2003; Iki et al., 2005; Sfakianos et al., 2007; Lin et al., 2013; 87 MacGillavry et al., 2016; Mikhaylova et al., 2018). Abl2 binds actin filaments cooperatively 88 (Wang et al., 2001) and increases the binding stoichiometry of cortactin for actin filaments 89 (MacGrath and Koleske, 2012b). These interactions significantly impact actin filament stability – 90 at saturated binding, Abl2 and cortactin each stabilize actin filaments (Courtemanche et al., 91 2015; Scherer et al., 2018), but mixtures of Abl2 and cortactin at concentrations far below 92 saturated binding also stabilize actin filaments (MacGrath and Koleske, 2012b; Courtemanche 93 et al., 2015). While Abl2 and cortactin synergize to stabilize actin filaments in vitro, it is unclear 94 whether or how they contribute to actin stability in neurons or how this mechanism might impact 95 dendritic spine shape or stability. 96 Here, we show that cortactin anchors Abl2 in dendritic spines via an 97 SH2:phosphotyrosine interface, and mutational disruption of this interface dislodges Abl2 from 98 spines. Depletion of either protein eliminates the stable actin pool in spines, as measured by 99 FRAP of GFP-actin. Disruption of this stable pool correlates with a significant loss of dendritic 100 spines. We find that a subset of spines remaining after Abl2 depletion exhibit increased spine 101 head widths, which is tightly associated with increased cortactin and GluN2B levels, and 102 retention of the stable actin pool. Finally, tonic increases in activity can rescue spine loss upon 103 Abl2 depletion by promoting cortactin enrichment in vulnerable spines that are otherwise lost in 104 basal conditions. Together, our data indicate that Abl2 and cortactin synergize to maintain 105 dendritic spine stable actin, which is critical for spine stability. 5 106 Materials and Methods: 107 Animals 108 All animal procedures were compliant with federal regulations and approved by the Animal Care 109 and Use Committees at Yale University, University of Maryland at Baltimore and Hussman 110 Institute for Autism. Balb/c mice were purchased from Charles River Laboratories. Animals were 111 housed and cared for in a Yale-sponsored OPRR approved animal facility. Neonatal mice of 112 both sexes were sacrificed for neuronal culture preparation. 113 114 Cell culture and transfections 115 HEK293 cells were plated in 6-well plates and maintained in high glucose DMEM (Invitrogen) 116 growth media supplemented with 1% pen/strep (Gibco), 2 mM L-glutamine (Gibco), and 10% 117 fetal bovine serum (Sigma-Aldrich). Primary neuronal cultures were prepared from postnatal day 118 1 mouse hippocampus as previously described (Lin et al., 2013). Neurons were maintained in 119 serum free media containing 1% pen/strep, 2 mM L-glutamine, and 2% B27-supplement (Gibco) 120 in Neurobasal media (NB-SFM) (Invitrogen).
Load more

Recommended publications
  • Exploring the Mechanisms Underlying Excitation/Inhibition Imbalance in Human Ipsc-Derived Models of ASD Lorenza Culotta1,3 and Peter Penzes1,2,3*
    Culotta and Penzes Molecular Autism (2020) 11:32 https://doi.org/10.1186/s13229-020-00339-0 REVIEW Open Access Exploring the mechanisms underlying excitation/inhibition imbalance in human iPSC-derived models of ASD Lorenza Culotta1,3 and Peter Penzes1,2,3* Abstract Autism spectrum disorder (ASD) is a range of neurodevelopmental disorders characterized by impaired social interaction and communication, and repetitive or restricted behaviors. ASD subjects exhibit complex genetic and clinical heterogeneity, thus hindering the discovery of pathophysiological mechanisms. Considering that several ASD-risk genes encode proteins involved in the regulation of synaptic plasticity, neuronal excitability, and neuronal connectivity, one hypothesis that has emerged is that ASD arises from a disruption of the neuronal network activity due to perturbation of the synaptic excitation and inhibition (E/I) balance. The development of induced pluripotent stem cell (iPSC) technology and recent advances in neuronal differentiation techniques provide a unique opportunity to model complex neuronal connectivity and to test the E/I hypothesis of ASD in human-based models. Here, we aim to review the latest advances in studying the different cellular and molecular mechanisms contributing to E/I balance using iPSC-based in vitro models of ASD. Keywords: Autism spectrum disorder, Induced pluripotent stem cell, Excitation/inhibition balance Background ASD can be classified into syndromic and non- Autism spectrum disorder (ASD) represents a spectrum of syndromic forms [4–7]. Syndromic ASD accounts for a early-onset neurodevelopmental disorders characterized by small percentage of total ASD cases; it typically occurs persistent deficits in social interaction and communication, with a clinical presentation in association with secondary as well as repetitive patterns of behavior and restricted inter- phenotypes and/or dysmorphic features [6].
    [Show full text]
  • Geometric Control of Frequency Modulation of Camp Oscillations Due to Calcium in Dendritic Spines
    Article Geometric Control of Frequency Modulation of cAMP Oscillations due to Calcium in Dendritic Spines Donya Ohadi1 and Padmini Rangamani1,* 1Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, California ABSTRACT The spatiotemporal regulation of cyclic adenosine monophosphate (cAMP) and its dynamic interactions with other second messengers such as calcium are critical features of signaling specificity required for neuronal development and connectivity. cAMP is known to contribute to long-term potentiation and memory formation by controlling the formation and regu- lation of dendritic spines. Despite the recent advances in biosensing techniques for monitoring spatiotemporal cAMP dynamics, the underlying molecular mechanisms that attribute to the subcellular modulation of cAMP remain unknown. In this work, we model the spatiotemporal dynamics of calcium-induced cAMP signaling pathway in dendritic spines. Using a three-dimensional reaction-diffusion model, we investigate the effect of different spatial characteristics of cAMP dynamics that may be responsible for subcellular regulation of cAMP concentrations. Our model predicts that the volume/surface ratio of the spine, regulated through the spine head size, spine neck size, and the presence of physical barriers (spine apparatus), is an important regulator of cAMP dynamics. Furthermore, localization of the enzymes responsible for the synthesis and degradation of cAMP in different compartments also modulates the oscillatory patterns of cAMP through exponential relationships. Our findings shed light on the significance of complex geometric and localization relationships for cAMP dynamics in dendritic spines. SIGNIFICANCE Dendritic spines are small signaling subcompartments along dendrites in neurons. They are the primary sites of postsynaptic activity. Here, we investigate how spine size and spatial organization of enzymes can change the dynamics of cyclic adenosine monophosphate, a second messenger interacting with calcium.
    [Show full text]
  • Identification and Functional Characterization of Rare SHANK2
    OPEN Molecular Psychiatry (2015) 20, 1489–1498 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp ORIGINAL ARTICLE Identification and functional characterization of rare SHANK2 variants in schizophrenia S Peykov1, S Berkel1, M Schoen2, K Weiss3, F Degenhardt4, J Strohmaier5, B Weiss1, C Proepper2, G Schratt3, MM Nöthen4,5, TM Boeckers2, M Rietschel6 and GA Rappold1,7 Recent genetic data on schizophrenia (SCZ) have suggested that proteins of the postsynaptic density of excitatory synapses have a role in its etiology. Mutations in the three SHANK genes encoding for postsynaptic scaffolding proteins have been shown to represent risk factors for autism spectrum disorders and other neurodevelopmental disorders. To address if SHANK2 variants are associated with SCZ, we sequenced SHANK2 in 481 patients and 659 unaffected individuals. We identified a significant increase in the number of rare (minor allele frequencyo1%) SHANK2 missense variants in SCZ individuals (6.9%) compared with controls (3.9%, P = 0.039). Four out of fifteen non-synonymous variants identified in the SCZ cohort (S610Y, R958S, P1119T and A1731S) were selected for functional analysis. Overexpression and knockdown-rescue experiments were carried out in cultured primary hippocampal neurons with a major focus on the analysis of morphological changes. Furthermore, the effect on actin polymerization in fibroblast cell lines was investigated. All four variants revealed functional impairment to various degrees, as a consequence of alterations in spine volume and clustering at synapses and an overall loss of presynaptic contacts. The A1731S variant was identified in four unrelated SCZ patients (0.83%) but not in any of the sequenced controls and public databases (P = 4.6 × 10 − 5).
    [Show full text]
  • Lysine-Specific Demethylase 1 Is Strongly Expressed in Poorly Differentiated Neuroblastoma: Implications for Therapy
    Published OnlineFirst February 17, 2009; DOI: 10.1158/0008-5472.CAN-08-1735 Research Article Lysine-Specific Demethylase 1 Is Strongly Expressed in Poorly Differentiated Neuroblastoma: Implications for Therapy Johannes H. Schulte,1 Soyoung Lim,3 Alexander Schramm,1 Nicolaus Friedrichs,3 Jan Koster,4 Rogier Versteeg,4 Ingrid Ora,4,5 Kristian Pajtler,1 Ludger Klein-Hitpass,2 Steffi Kuhfittig-Kulle,1 Eric Metzger,6 Roland Schu¨le,6 Angelika Eggert,1 Reinhard Buettner,3 and Jutta Kirfel3 1Department of Paediatric Oncology and Hematology, University Children’s Hospital Essen; 2Institute of Cell Biology, University Hospital of Essen, Essen, Germany; 3Institute of Pathology, University of Bonn, Bonn, Germany; 4Department of Human Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 5Department of Pediatric Oncology and Hematology, Lund University Hospital, Lund, Sweden; 6Center for Clinical Research, Freiburg University Medical Center, Freiburg, Germany Abstract often fatally progresses regardless of multimodal therapy (1, 2). Aberrant epigenetic changes in DNA methylation and histone Therefore, the identification of novel drug targets and development acetylation are hallmarks of most cancers, whereas histone of new therapeutic options are urgently needed. Patterns methylation was previously considered to be irreversible and characteristic of aggressive neuroblastoma have been identified less versatile. Recently, several histone demethylases were via high-throughput analysis, including expression profiling (3, 4) identified catalyzing the removal of methyl groups from histone and array CGH (5–7), with NMYC amplification, 1p36 and 11q H3 lysine residues and thereby influencing gene expression. deletion (8), and 17q gain being the most prominent chromosomal Neuroblastomas continue to remain a clinical challenge alterations.
    [Show full text]
  • Fear and Safety Learning Differentially Affect Synapse Size and Dendritic Translation in the Lateral Amygdala
    Fear and safety learning differentially affect synapse size and dendritic translation in the lateral amygdala Linnaea E. Ostroffa,1, Christopher K. Caina, Joseph Bedonta,b, Marie H. Monfilsa, and Joseph E. LeDouxa,c aCenter for Neural Science, New York University, New York, NY 10003; bDepartment of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and cEmotional Brain Institute, Nathan S. Kline Institute for Psychiatry Research, Orangeburg, NY 10962 Edited by Richard L. Huganir, Johns Hopkins University School of Medicine, Baltimore, MD, and approved April 13, 2010 (received for review November 19, 2009) Fear learning is associated with changes in synapse strength in the clearly involved in hippocampal LTP and is suspected to occur with lateral amygdala (LA). To examine changes in LA dendritic spine fear conditioning, although this has not been directly observed structure with learning, we used serial electron microscopy to re- (22–25). We found that there were more polyribosomes in LA construct dendrites after either fear or safety conditioning. The dendrites after fear conditioning and that their presence in spines spine apparatus, a smooth endoplasmic reticulum (sER) specializa- was differentially associated with changes in synapse size. tion found in very large spines, appeared more frequently after fear conditioning. Fear conditioning was associated with larger synapses Results on spines that did not contain a spine apparatus, whereas safety Behavioral Evidence for Single-Session Fear or Safety Learning. To conditioning resulted in smaller synapses on these spines. Synapses compare spine morphology in adult rats during consolidation of on spines with a spine apparatus were smaller after safety con- fear learning, we designed and tested two training protocols of ditioning but unchanged with fear conditioning, suggesting a ceil- equal length with equal numbers of tone and shock pre- ing effect.
    [Show full text]
  • Ultrastructural Analysis of Spine Plasticity 11
    Ultrastructural Analysis of Spine Plasticity 11 Ultrastructural Analysis of Spine Plasticity J N Bourne and K M Harris, Medical College of from the shaft to spines. Similarly, endosomal compart- Georgia, Augusta, GA, USA ments including coated pits and vesicles, large vesicles, ã 2009 Elsevier Ltd. All rights reserved. tubules, and multivesicular bodies are restricted to a subpopulation of dendritic spines that differs from spines that contain SER. Mitochondria rarely occur in dendritic spines and are usually restricted to those Introduction that are very large, complex, and highly branched. Dendritic spines are small protrusions that serve as the However, during periods of active synapse formation major site of excitatory synaptic transmission in the and remodeling in cultured neurons, mitochondria brain. The shape and density of spines can be affected can localize to smaller dendritic spines. by numerous factors, including developmental stage, Postsynaptic Targets experimental preparation, temperature, exposure to enriched environments, and neuronal pathology. In Evaluation of dendritic spine structure readily reveals addition, physiological models of learning, including them to be the major postsynaptic target of excitatory long-term potentiation (LTP) and long-term depres- synaptic input (Figure 2(a)). Since all dendritic spines sion (LTD), have indicated that alterations in synaptic have at least one excitatory synapse on their head, ultrastructure may underlie the storage of information more spines mean more synapses and accordingly in the brain. more point-to-point connections in a neuronal ensemble involving spiny neurons. The size of the Spine Structure and Function spine head also influences the amount of synaptic input, because larger spines are more sensitive to Spine Shape glutamate, the major excitatory neurotransmitter in the brain.
    [Show full text]
  • Structural Variation Targets Neurodevelopmental Genes and Identifies SHANK2 As a Tumor
    bioRxiv preprint doi: https://doi.org/10.1101/572248; this version posted March 13, 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. Structural Variation in Neuroblastoma Lopez, Conkrite, et al. Structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma Gonzalo Lopez1,2+, Karina L. Conkrite1,2+, Miriam Doepner1,2, Komal S. Rathi3, Apexa Modi1,2,10, Zalman Vaksman1-3, Lance M. Farra1,2, Eric Hyson1,2, Moataz Noureddine1,2, Jun S. Wei4, Malcolm A. Smith9, Shahab Asgharzadeh5,6, Robert C. Seeger5,6, Javed Khan4, Jaime Guidry Auvil8, Daniela S. Gerhard8, John M. Maris1-2,10,11, Sharon J. Diskin1-3,10,11* 1Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 2Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 3Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 4Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA 5Division of Hematology, Oncology and Blood and Marrow Transplantation, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. 6The Saban Research Institute, Children’s Hospital of Los Angeles, Los Angeles, CA, USA. 7Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 8Office of Cancer Genomics, National Cancer Institute, Bethesda, MD, USA. 9Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. 10Genomics and Computational Biology, Biomedical Graduate Studies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
    [Show full text]
  • Homer1 Promotes Dendritic Spine Growth Through Ankyrin-G and Its Loss Reshapes the Synaptic Proteome
    Molecular Psychiatry (2021) 26:1775–1789 https://doi.org/10.1038/s41380-020-00991-1 ARTICLE Homer1 promotes dendritic spine growth through ankyrin-G and its loss reshapes the synaptic proteome 1 1 2 1,5 2 Sehyoun Yoon ● Nicolas H. Piguel ● Natalia Khalatyan ● Leonardo E. Dionisio ● Jeffrey N. Savas ● Peter Penzes 1,3,4 Received: 22 February 2020 / Revised: 24 November 2020 / Accepted: 7 December 2020 / Published online: 4 January 2021 © The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature 2021. This article is published with open access Abstract Homer1 is a synaptic scaffold protein that regulates glutamatergic synapses and spine morphogenesis. HOMER1 knockout (KO) mice show behavioral abnormalities related to psychiatric disorders, and HOMER1 has been associated with psychiatric disorders such as addiction, autism disorder (ASD), schizophrenia (SZ), and depression. However, the mechanisms by which it promotes spine stability and its global function in maintaining the synaptic proteome has not yet been fully investigated. Here, we used computational approaches to identify global functions for proteins containing the Homer1-interacting PPXXF motif within the postsynaptic compartment. Ankyrin-G was one of the most topologically important nodes in the postsynaptic peripheral 1234567890();,: 1234567890();,: membrane subnetwork, and we show that one of the PPXXF motifs, present in the postsynaptically-enriched 190 kDa isoform of ankyrin-G (ankyrin-G 190), is recognized by the EVH1 domain of Homer1. We use proximity ligation combined with super- resolution microscopy to map the interaction of ankyrin-G and Homer1 to distinct nanodomains within the spine head and correlate them with spine head size.
    [Show full text]
  • A Biochemist's View of Long-Term Potentiation Erik D
    Downloaded from learnmem.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW A Biochemist's View of Long-term Potentiation Erik D. Roberson, Joey D. English, and J. David Sweatt ~ Division of Neur0science Bayl0r College of Medicine Houston, Texas 77030 Abstract teractions. Explanations of LTP in terms of changes in synaptic structure (Edwards 1995) or on the This review surveys the molecular basis of silent synapses becoming functional (Isaac mechanisms of long-term potentiation et al. 1995) recently have been proposed. It is (LTP) from the point of view of a worth keeping in mind, though, that even those biochemist. On the basis of available data, processes must have some underlying biochemical LTP in area CA1 of the hippocampus is basis, for any persisting change in a neuron's func- divided into three phases--initial, early, and tion must be produced by a persisting change in late---and the mechanisms contributing to one or more of its proteins [or, perhaps less likely, the induction and expression of each phase in persisting changes to one of its two other mac- are examined. We focus on evidence for the romolecular complexes, DNA and RNA (see Crick involvement of various second messengers 1984)]. Thus, an explanation of LTP in terms of and their effectors as well as the biochemical changes is not mutually exclusive of biochemical strategies employed in each an explanation based on, for example, structure; in phase to convert a transient signal into a fact, a biochemical explanation is a necessary part lasting change in the neuron.
    [Show full text]
  • 8P23.2-Pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature
    G C A T T A C G G C A T genes Article 8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature Ilaria Catusi 1,* , Maria Garzo 1 , Anna Paola Capra 2 , Silvana Briuglia 2 , Chiara Baldo 3 , Maria Paola Canevini 4 , Rachele Cantone 5, Flaviana Elia 6, Francesca Forzano 7, Ornella Galesi 8, Enrico Grosso 5, Michela Malacarne 3, Angela Peron 4,9,10 , Corrado Romano 11 , Monica Saccani 4 , Lidia Larizza 1 and Maria Paola Recalcati 1 1 Istituto Auxologico Italiano, IRCCS, Laboratory of Medical Cytogenetics and Molecular Genetics, 20145 Milan, Italy; [email protected] (M.G.); [email protected] (L.L.); [email protected] (M.P.R.) 2 Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, 98100 Messina, Italy; [email protected] (A.P.C.); [email protected] (S.B.) 3 UOC Laboratorio di Genetica Umana, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; [email protected] (C.B.); [email protected] (M.M.) 4 Child Neuropsychiatry Unit—Epilepsy Center, Department of Health Sciences, ASST Santi Paolo e Carlo, San Paolo Hospital, Università Degli Studi di Milano, 20142 Milan, Italy; [email protected] (M.P.C.); [email protected] (A.P.); [email protected] (M.S.) 5 Medical Genetics Unit, Città della Salute e della Scienza University Hospital, 10126 Turin, Italy; [email protected] (R.C.); [email protected] (E.G.) 6 Unit of Psychology, Oasi Research Institute-IRCCS,
    [Show full text]
  • LGI1–ADAM22–MAGUK Configures Transsynaptic Nanoalignment for Synaptic Transmission and Epilepsy Prevention
    LGI1–ADAM22–MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention Yuko Fukataa,b,1, Xiumin Chenc,d,1, Satomi Chikenb,e, Yoko Hiranoa,f, Atsushi Yamagatag, Hiroki Inahashia, Makoto Sanboh, Hiromi Sanob,e, Teppei Gotoh, Masumi Hirabayashib,h, Hans-Christian Kornaui,j, Harald Prüssi,k, Atsushi Nambub,e, Shuya Fukail, Roger A. Nicollc,d,2, and Masaki Fukataa,b,2 aDivision of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi 444-8787, Japan; bDepartment of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Aichi 444-8585, Japan; cDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158; dDepartment of Physiology, University of California, San Francisco, CA 94158; eDivision of System Neurophysiology, Department of System Neuroscience, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi 444-8585, Japan; fDepartment of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; gLaboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Kanagawa 230-0045, Japan; hCenter for Genetic Analysis of Behavior, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki 444-8787, Japan; iGerman Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany; jNeuroscience Research Center, Cluster NeuroCure, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; kDepartment of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; and lDepartment of Chemistry, Graduate School of Science, Kyoto University, 606-8502 Kyoto, Japan Contributed by Roger A. Nicoll, December 1, 2020 (sent for review October 29, 2020; reviewed by David S.
    [Show full text]
  • Dendritic Spine Geometry and Spine Apparatus Organization Govern the Spatiotemporal Dynamics of Calcium
    bioRxiv preprint doi: https://doi.org/10.1101/386367; this version posted May 29, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Dendritic spine geometry and spine apparatus organization govern the spatiotemporal dynamics of calcium Miriam Bell1, Tom Bartol2, Terrence Sejnowski2,3, and Padmini Rangamani1,* 1 Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, United States 2 Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, United States 3 Division of Biological Sciences, University of California, San Diego, San Diego, United States * [email protected]. Abstract Dendritic spines are small subcompartments that protrude from the dendrites of neurons and are important for signaling activity and synaptic communication. These subcompartments have been characterized to have different shapes. While it is known that these shapes are associated with spine function, the specific nature of these shape-function relationships is not well understood. In this work, we systematically investigated the relationship between the shape and size of both the spine head and spine apparatus, a specialized endoplasmic reticulum compartment in the spine head, in modulating rapid calcium dynamics using mathematical modeling. We developed a spatial multi-compartment reaction-diffusion model of calcium dynamics in three dimensions with various flux sources including N-methyl-D-aspartate receptors (NMDAR), voltage sensitive calcium channels (VSCC), and different ion pumps on the plasma membrane.
    [Show full text]