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Modulation of Glutamate AMPA Receptors by Adenosine, in Physiological and Hypoxic/Ischemic Conditions

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Modulation of Glutamate AMPA Receptors by Adenosine, in Physiological and Hypoxic/Ischemic Conditions UNIVERSIDADE D E L ISBOA Instituto de Farmacologia e Neurociências, Faculdade de Medicina, e Unidade de Neurociências, Instituto de Medicina Molecular Modulation of glutamate AMPA receptors by adenosine, in physiological and hypoxic/ischemic conditions Raquel Alice da Silva Baptista Dias Doutoramento em Ciências Biomédicas Especialidade em Neurociências Lisboa, 2011 ii \\UNIVERSIDADE D E L ISBOA Instituto de Farmacologia e Neurociências, Faculdade de Medicina, e Unidade de Neurociências, Instituto de Medicina Molecular Modulation of glutamate AMPA receptors by adenosine, in physiological and hypoxic/ischemic conditions Raquel Alice da Silva Baptista Dias Tese Orientada pela Professora Doutora Ana Maria Sebastião Doutoramento em Ciências Biomédicas Especialidade em Neurociências Todas as afirmações efectuadas no presente documento são da exclusiva responsabilidade do seu autor, não cabendo qualquer responsabilidade à Faculdade de Medicina pelos conteúdos nele apresentados. Lisboa, 2011 iii A impressão desta dissertação foi aprovada pelo Concelho Científico da Faculdade de Medicina de Lisboa em reunião de 19 de Abril de 2011. iv The experimental work contained in this thesis was performed at the Institute of Pharmacology and Neuroscience, Faculty of Medicine and Unit of Neurosciences, Institute of Molecular Medicine, under the supervision of Professor Ana Maria Ferreira de Sousa Sebastião. O trabalho experimental constante da presente tese foi realizado no Instituto de Farmacologia e Neurociências, Faculdade de Medicina e Unidade de Neurociências, Instituto de Medicina Molecular, sob orientação da Professora Doutora Ana Maria Ferreira de Sousa Sebastião. v vi Para o meu avô António. Pelas tardes de Verão a fazer bolos de serradura e a martelar pregos tortos, no sótão. vii Publications The scientific content described in the present thesis has been the subject of two original articles, listed below. Regarding the second manuscript, only the experiments performed by the author were included in the corresponding results chapter, although reference to complementary results is made in their discussion. • Dias RB , Ribeiro JA, Sebastião AM. Enhancement of AMPA currents and GluR1 membrane expression through PKA- coupled adenosine A 2A receptors. Hippocampus, 2010 , epub ahead of print, PMID: 21080412 • Moidunny S, Dias RB , Wesseling E, Sekino Y, Boddeke HW, Sebastião AM, Biber K. Interleukin-6-type cytokines in neuroprotection and neuromodulation: oncostatin M, but not leukemia inhibitory factor, requires neuronal adenosine A1 receptor function. Journal of Neurochemistry, 2010, 114 :1667- 77 viii Table of Contents 1 Introduction ........................................................................................... 1 1.1 AMPA receptors........................................................................................ 4 1.1.1 Alternative splicing of AMPA receptor subunits ............................... 6 1.1.2 RNA Editing of AMPA Receptor subunits ........................................ 8 1.1.3 AMPA receptor subunit phosphorylation......................................... 11 1.1.4 AMPA receptor trafficking .............................................................. 14 1.1.5 Synaptic Plasticity............................................................................ 21 1.1.5.1 AMPA receptors in Synaptic Plasticity: NMDA receptor- dependent LTP in the CA1 area ................................................................... 25 1.2 Excitotoxicity: AMPA receptors in ischemia.......................................... 30 1.3 Neuromodulation by adenosine............................................................... 38 1.3.1 Adenosine receptors ......................................................................... 39 1.3.2 Regulation of extracellular adenosine levels.................................... 43 2 Aim........................................................................................................ 50 3 Techniques............................................................................................ 51 3.1 Patch-clamp Recordings.......................................................................... 51 3.1.1 Applications and technical pitfalls of the patch-clamp technique .... 56 3.2 Acute brain slice preparations ................................................................. 66 3.2.1 The hippocampal slice model........................................................... 67 3.3 Western Blot analysis.............................................................................. 73 3.3.1 Gel Electrophoresis .......................................................................... 76 ix 3.3.2 Protein Transfer to a membrane (blot) ............................................. 78 3.3.3 Protein Detection.............................................................................. 80 3.4 Protein Biotinylation ............................................................................... 81 4 Materials and Methods ....................................................................... 86 4.1 Tissue Preparation................................................................................... 86 4.2 Patch-clamp recordings ........................................................................... 87 4.2.1 AMPA-evoked postsynaptic currents............................................... 88 4.2.2 mEPSC Recordings.......................................................................... 88 4.2.3 EPSC recordings and LTP................................................................ 89 4.2.4 Hypoxia induction............................................................................ 90 4.2.5 Oxygen/glucose deprivation............................................................. 90 4.3 Protein biotinylation................................................................................ 91 4.4 Immunoblot analysis ............................................................................... 92 4.5 Drugs....................................................................................................... 93 4.6 Preparation of recombinant cytokine samples......................................... 93 4.7 Statistical Analysis .................................................................................. 94 5 Results................................................................................................... 95 5.1 Activation of A 2A Adenosine Receptors Facilitates AMPA receptor- mediated responses in CA1 Pyramidal Neurons with consequences for synaptic plasticity ................................................................................................................ 95 5.2 A2A Adenosine receptor activation Modulates Ischemia-induced Plasticity in the CA1 area.................................................................................................... 133 5.3 Crosstalk between immunoregulatory cytokines of the Interleukin-6 family and neuronal adenosine A 1 receptor function: implications for synaptic transmission regulation and neuroprotection from excitotoxic damage .............. 150 6 General Conclusions.......................................................................... 165 x 7 Future Perspectives ........................................................................... 168 8 Acknowledgements............................................................................ 171 9 References .......................................................................................... 175 xi Figure index Figure 1.1. Steps in the process of chemical synaptic transmission………......5 Figure 1.1.1. Structure and composition of AMPA receptors………………...7 Figure 1.1.1.1. Localization of protein binding and phosphorylation sites in the C terminal of AMPA receptor subunits………………………………......9 Figure 1.1.2.1. Model accounting for the differential dependence of calcium permeability and inward rectification on GluR2 abundance...………………11 Figure 1.1.4.1. Schematic representation of the role played by different interacting proteins upon AMPAR trafficking……………………......……..16 Figure 1.1.4.2. Constitutive and regulated trafficking of AMPARs at synapses……………………………………………………………….…….18 Figure 1.1.4.3. A Model of Basal AMPA Receptor Trafficking…………….20 Figure 1.1.4.4. Two-step model for synaptic delivery of AMPARs during LTP…………………………………………………………………….…….21 Figure 1.1.5.1.1. NMDA and AMPA receptors regulate synapse formation, growth and stabilization……………………………………………….……..28 Figure 1.1.5.1.2. Changes in the subunit composition of AMPARs during LTP in CA1 pyramidal neurons……………………………………..…….………29 Figure 1.2.1. Excitotoxic cell death………………………………………….33 Figure 1.3.1.1. Adenosine receptors can couple to several G proteins………43 Figure 1.3.1.2. Distribution of high affinity adenosine receptors (A 1, A 2A and human A 3) in the rat brain…………………………………..……...………..44 xii Figure 1.3.2.1. The metabolism of extracellular ATP is regulated by several ectonucleotidases……………………………...……………………………..45 Figure 1.3.2.2. Receptor complexes activated by different members of the IL- 6 cytokine family…………………………………………………………….48 Figure 3.1.1. Patch-clamp recordings can be performed under four different configurations………………………………...…………..………………….56 Figure 3.1.2. Two-electrode voltage-clamp schematic circuit………...…….59 Figure 3.1.3. Schematic diagram of the headstage current/voltage amplifier……………………………………………………………….……..60 Figure 3.1.4. Test pulses produce different current responses as one proceeds through the establishment of a whole-cell
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