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Ethanol-Induced Changes in Brain of Transgenic Mice Overexpressing DYRK1A

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Abstract

Alcoholism is a chronic relapsing disorder defined by loss of control over excessive consumption of ethanol despite damaging effects on the liver and brain. We previously showed that the overexpression in mice of Dyrk1A (TgDyrk1A, for dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1A) reduces the severity of alcohol mediated liver injury. Ethanol consumption has also been associated with increased brain glutamate concentration that led to therapies targeting glutamatergic receptors and normalization of glutamatergic neurotransmission. Interestingly, mice overexpressing Dyrk1A (TgDyrk1A mice) present a reduction of glutamatergic brain transmission, which we propose could be protective against alcohol intake. To answer this question, we investigated the ethanol preference in TgDyrk1A mice using a two-bottle choice paradigm. TgDyrk1A mice showed a non-significant decrease of voluntary ethanol intake and ethanol preference compared with wild-type mice. At the peripheral level, mice overexpressing Dyrk1A show lower ethanol plasma levels, indicating a faster ethanol metabolism. At the end of the protocol, lasting 21 days, brains were extracted for protein analysis. Ethanol reduced levels of the synaptic protein PSD-95 and increased the glutamate decarboxylase GAD65, specifically in the cortex of TgDyrk1A mice. Our results suggest that overexpression of DYRK1A may cause different ethanol-induced changes in the brain.

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Abbreviations

BEC:

blood ethanol concentrations

DYRK1A:

Dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1A

GABA:

Gamma amino butyric acid

GAD:

Glutamic acid decarboxylase

GLAST:

Glutamate aspartate transporter

GLT1:

Glutamate transporter-1

GluN2A:

Glutamate ionotropic receptor NMDA type subunit 2A

NMDA:

N-methyl-D-aspartate

NMDAR:

NMDA receptor

PSD-95:

Post-synaptic density 95

VGAT1:

Vesicular transporter of GABA

VGLUT1:

Vesicular transporter of glutamate

WT:

Wild-type

References

  1. Spanagel R (2018) Aberrant choice behavior in alcoholism. Science 360:1298–1299

    Article  CAS  PubMed  Google Scholar 

  2. Harper C (2009) The neuropathology of alcohol-related brain damage. Alcohol Alcohol 44:136–140

    Article  CAS  PubMed  Google Scholar 

  3. Smith JE, Co C, McIntosh S, Cunningham CC (2008) Chronic binge-like moderate ethanol drinking in rats results in widespread decreases in brain serotonin, dopamine, and norepinephrine turnover rates reversed by ethanol intake. J Neurochem 105:2134–2155

    Article  CAS  PubMed  Google Scholar 

  4. Spanagel R (2009) Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol Rev 89:649–705

    Article  CAS  PubMed  Google Scholar 

  5. Spanagel R, Pendyala G, Abarca C, Zghoul T, Sanchis-Segura C, Magnone MC, Lascorz J, Depner M et al (2005) The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat Med 11:35–42

    Article  CAS  PubMed  Google Scholar 

  6. Spanagel R, Kiefer F (2008) Drugs for relapse prevention of alcoholism: ten years of progress. Trends Pharmacol Sci 29:109–115

    Article  CAS  PubMed  Google Scholar 

  7. Holmes A, Spanagel R, Krystal JH (2013) Glutamatergic targets for new alcohol medications. Psychopharmacology 229:539–554

    Article  CAS  PubMed  Google Scholar 

  8. Abrahao KP, Salinas AG, Lovinger DM (2017) Alcohol and the brain: neuronal molecular targets, synapses, and circuits. Neuron 96:1223–1238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. McCool BA (2011) Ethanol modulation of synaptic plasticity. Neuropharmacology 61:1097–1108

    Article  CAS  PubMed  Google Scholar 

  10. Altafaj X, Ortiz-Abalia J, Fernandez M, Potier MC, Laffaire J, Andreu N, Dierssen M, Gonzalez-Garcia C et al (2008) Increased NR2A expression and prolonged decay of NMDA-induced calcium transient in cerebellum of TgDyrk1A mice, a mouse model of down syndrome. Neurobiol Dis 32:377–384

    Article  CAS  PubMed  Google Scholar 

  11. Souchet B, Guedj F, Sahun I, Duchon A, Daubigney F, Badel A, Yanagawa Y, Barallobre MJ et al (2014) Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage. Neurobiol Dis 69:65–75

    Article  CAS  PubMed  Google Scholar 

  12. Souchet B, Guedj F, Penke-Verdier Z, Daubigney F, Duchon A, Herault Y, Bizot JC, Janel N et al (2015) Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models. Front Behav Neurosci 9:267

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Lee SE, Lee Y, Lee GH (2019) The regulation of glutamic acid decarboxylases in GABA neurotransmission in the brain. Arch Pharm Res 42:1031–1039

    Article  CAS  PubMed  Google Scholar 

  14. Dang T, Duan WY, Yu B, Tong DL, Cheng C, Zhang YF, Wu W, Ye K et al (2018) Autism-associated Dyrk1a truncation mutants impair neuronal dendritic and spine growth and interfere with postnatal cortical development. Mol Psychiatry 23:747–758

    Article  CAS  PubMed  Google Scholar 

  15. Benavides-Piccione R, Dierssen M, Ballesteros-Yanez I, Martinez de Lagran M, Arbones M, Fotaki V, De Felipe J, Elston G (2005) Alterations in the phenotype of neocortical pyramidal cells in the Dyrk1A+/− mouse. Neurobiol Dis 20:115–122

    Article  CAS  PubMed  Google Scholar 

  16. Arranz J, Balducci E, Arató K, Sánchez-Elexpuru G, Najas S, Parras A, Rebollo E, Pijuan I et al (2019) Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome. Neurobiol Dis 127:210–222

    Article  CAS  PubMed  Google Scholar 

  17. Fotaki V, Dierssen M, Alcantara S, Martinez S, Marti E, Casas C, Visa J, Soriano E et al (2002) Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice. Mol Cell Biol 22:6636–6647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Renon M, Legrand B, Blanc E, Daubigney F, Bokobza C, Mortreux M, Paul JL, Delabar JM et al (2016) Impact of Dyrk1A level on alcohol metabolism. Biochim Biophys Acta 1862:1495–1503

    Article  CAS  PubMed  Google Scholar 

  19. Guedj F, Pereira PL, Najas S, Barallobre MJ, Chabert C, Souchet B, Sebrie C, Verney C et al (2012) DYRK1A: A master regulatory protein controlling brain growth. Neurobiol Dis 46:190–203

    Article  CAS  PubMed  Google Scholar 

  20. Becker JB, Hu M (2008) Sex differences in drug abuse. Front Neuroendocrinol 29:36–47

    Article  CAS  PubMed  Google Scholar 

  21. Crabbe JC, Phillips TJ, Feller DJ, Hen R, Wenger CD, Lessov CN, Schafer GL (1996) Elevated alcohol consumption in null mutant mice lacking 5-HT1B serotonin receptors. Nat Genet 14:98–101

    Article  CAS  PubMed  Google Scholar 

  22. Kelai S, Renoir T, Chouchana L, Saurini F, Hanoun N, Hamon M, Lanfumey L (2008) Chronic voluntary ethanol intake hypersensitizes 5-HT(1A) autoreceptors in C57BL/6J mice. J Neurochem 107:1660–1670

    Article  CAS  PubMed  Google Scholar 

  23. Cui C, Noronha A, Morikawa H, Alvarez VA, Stuber GD, Szumlinski KK, Kash TL, Roberto M et al (2013) New insights on neurobiological mechanisms underlying alcohol addiction. Neuropharmacology 67:223–232

    Article  CAS  PubMed  Google Scholar 

  24. Kroener S, Mulholland PJ, New NN, Gass JT, Becker HC, Chandler LJ (2012) Chronic alcohol exposure alters behavioral and synaptic plasticity of the rodent prefrontal cortex. PLoS One 7:e37541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dierssen M, de Lagrán MM (2006) DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A): a gene with dosage effect during development and neurogenesis. ScientificWorldJournal. 6:1911–1922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Martinez de Lagran M, Benavides-Piccione R, Ballesteros-Yanez I, Calvo M, Morales M, Fillat C, Defelipe J, Ramakers GJ et al (2012) Dyrk1A influences neuronal morphogenesis through regulation of cytoskeletal dynamics in mammalian cortical neurons. Cereb Cortex 22:2867–2877

    Article  CAS  PubMed  Google Scholar 

  27. Ruiz-Mejias M, Martinez de Lagran M, Mattia M, Castano-Prat P, Perez-Mendez L, Ciria-Suarez L, Gener T, Sancristobal B et al (2016) Overexpression of Dyrk1A, a down syndrome candidate. Decreases Excitability and Impairs Gamma Oscillations in the Prefrontal Cortex J Neurosci 36:3648–3659

    CAS  PubMed  Google Scholar 

  28. Grau C, Arató K, Fernández-Fernández JM, Valderrama A, Sindreu C, Fillat C, Ferrer I, de la Luna S et al (2014) DYRK1A-mediated phosphorylation of GluN2A at Ser(1048) regulates the surface expression and channel activity of GluN1/GluN2A receptors. Front Cell Neurosci 8:331

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Varodayan FP, Sidhu H, Kreifeldt M, Roberto M, Contet C (2018) Morphological and functional evidence of increased excitatory signaling in the prelimbic cortex during ethanol withdrawal. Neuropharmacology 133:470–480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Howell MD, Gottschall PE (2012) Altered synaptic marker abundance in the hippocampal stratum oriens of Ts65Dn mice is associated with exuberant expression of versican. ASN Neuro 4:e00073

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Zhang J, Saur T, Duke AN, Grant SG, Platt DM, Rowlett JK, Isacson O, Yao WD (2014) Motor impairments, striatal degeneration, and altered dopamine-glutamate interplay in mice lacking PSD-95. J Neurogenet 28:98–111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Camp MC, Feyder M, Ihne J, Palachick B, Hurd B, Karlsson RM, Noronha B, Chen YC et al (2011) A novel role for PSD-95 in mediating ethanol intoxication, drinking and place preference. Addict Biol 16:428–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kleschevnikov AM, Belichenko PV, Gall J, George L, Nosheny R, Maloney MT, Salehi A, Mobley WC (2012) Increased efficiency of the GABAA and GABAB receptor-mediated neurotransmission in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis 45:683–691

    Article  CAS  PubMed  Google Scholar 

  34. Blednov YA, Walker DL, Lyer SV, Homanics G, Harris AR (2010) Mice lacking Gad2 show altered behavioral effects of ethanol, flurazepam and gabaxadol. Addict Biol 15:45–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Melendez RI, Hicks MP, Cagle SS, Kalivas PW (2005) Ethanol exposure decreases glutamate uptake in the nucleus accumbens. Alcohol Clin Exp Res 29:326–333

    Article  CAS  PubMed  Google Scholar 

  36. Kryger R, Wilce PA (2010) The effects of alcoholism on the human basolateral amygdala. Neuroscience 167:361–371

    Article  CAS  PubMed  Google Scholar 

  37. Bellocchio EE, Reimer RJ, Fremeau RT Jr, Edwards RH (2000) Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. Science 289:957–960

    Article  CAS  PubMed  Google Scholar 

  38. Takamori S, Rhee JS, Rosenmund C, Jahn R (2000) Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons. Nature 407:189–194

    Article  CAS  PubMed  Google Scholar 

  39. Ponomarev I, Wang S, Zhang L, Harris RA, Mayfield RD (2012) Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence. J Neurosci 32:1884–1897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kashem MA, Sultana N, Pow DV, Balcar VJ (2019) GLAST (GLutamate and ASpartate Transporter) in human prefrontal cortex; interactome in healthy brains and the expression of GLAST in brains of chronic alcoholics. Neurochem Int 125:111–116

    Article  CAS  PubMed  Google Scholar 

  41. Rao PS, Sari Y (2014) Effects of ceftriaxone on chronic ethanol consumption: a potential role for xCT and GLT1 modulation of glutamate levels in male P rats. J Mol Neurosci 54:71–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Alhaddad H, Kim NT, Aal-Aaboda M, Althobaiti YS, Leighton J, Boddu SH, Wei Y, Sari Y (2014) Effects of MS-153 on chronic ethanol consumption and GLT1 modulation of glutamate levels in male alcohol-preferring rats. Front Behav Neurosci 8:366

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Sari Y, Sreemantula SN (2012) Neuroimmunophilin GPI-1046 reduces ethanol consumption in part through activation of GLT1 in alcohol-preferring rats. Neuroscience 227:327–335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ezquer F, Quintanilla ME, Morales P, Santapau D, Ezquer M, Kogan MJ, Salas-Huenuleo E, Herrera-Marschitz M et al (2019) Intranasal delivery of mesenchymal stem cell-derived exosomes reduces oxidative stress and markedly inhibits ethanol consumption and post-deprivation relapse drinking. Addict Biol 24:994–1007

    Article  CAS  PubMed  Google Scholar 

  45. Ahn KJ, Jeong HK, Choi HS, Ryoo SR, Kim YJ, Goo JS, Choi SY, Han JS et al (2006) DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects. Neurobiol Dis 22:463–472

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Dr. Laurence Lanfumey for the helpful discussion. We thank the platform accommodation and animal testing of the animal house at the Institute Jacques Monod (University Paris Diderot) and the FlexStation3 Facility.

Funding

This work was supported by the IREB association. The group of MD is supported by the CRG Severo Ochoa excellence grant (SEV-2012-0208), the CIBER of Rare Diseases, and the “Secretaria d’Universitats i Recerca del Departament d’Economia I Coneixement de la Generalitat de Catalunya” (Grups consolidats 2017SGR595). We also acknowledge the support of the Spanish Ministry of Science, Innovation and Universities (MSIU) to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya.

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Author notes

  1. Marta Fructuoso and Yu Chen Gu contributed equally to this work.

Authors and Affiliations

  1. Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Pompeu Fabra University (Universitat Pompeu Fabra, UPF), 08003, Barcelona, Spain

    Marta Fructuoso, Maria Martinez de Lagran & Mara Dierssen

  2. Institut du Cerveau et la Moelle épinière, ICM, INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Paris, France

    Marta Fructuoso

  3. Université de Paris, BFA, UMR 8251, CNRS, F-75013, Paris, France

    Yu Chen Gu, Nadim Kassis & Nathalie Janel

  4. Human Pharmacology and Clinical Neurosciences Research Group, Neurosciences Research Program, Hospital Del Mar Medical Research Institute (IMIM), 08003, Barcelona, Spain

    Mara Dierssen

  5. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    Mara Dierssen

  6. Department of Statistics and Operations Research, Universitat Politècnica de Catalunya BarcelonaTech, Barcelona, Spain

    Mara Dierssen

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  1. Marta Fructuoso
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  2. Yu Chen Gu
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Contributions

MD and NJ designed study; MF, YCG, NK, and MML performed research; MF, YCG, MD, and NJ analyzed data; MD and NJ wrote the paper.

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Correspondence to Nathalie Janel.

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Fructuoso, M., Gu, Y.C., Kassis, N. et al. Ethanol-Induced Changes in Brain of Transgenic Mice Overexpressing DYRK1A. Mol Neurobiol 57, 3195–3205 (2020). https://doi.org/10.1007/s12035-020-01967-6

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