The role of adenosine as an endogenous neuromodulator is well established, but the mechanism(s) mediating the extensive modulatory and regulatory actions of adenosine have not yet been fully elucidated. In fact, although adenosine, through activation of adenosine A1 and A2A receptors, has been demonstrated as neuroprotective or neurodegenerative, respectively, little is known about the mechanism by which adenosine mediates these actions. In the hippocampus, essential physiological processes rely on adenosine signaling, including regulation of long-term potentiation (LTP) and long-term depression (LTD). Neuromodulation by adenosine is dominantly inhibitory in the hippocampus, mediated by the abundant and high-affinity adenosine A1 receptor. In ischemia and hypoxia, A1 receptor activation induces rapid synaptic depression which is mediated by multiple signaling pathways including the induction of excitatory AMPA glutamate receptor internalization, which inhibits synaptic transmission in the hippocampus. Considerable effort has been devoted to investigating the role of adenosine in ischemic stroke, due to the fact that in cerebral ischemia or hypoxia, extracellular levels of adenosine increase dramatically. This thesis explores the functional consequences of adenosine signaling in hypoxia and ischemia, which mediate GluA1 AMPA receptor subunit internalization. Three major serine/threonine protein phosphatases (PPs), PP1, PP2A, and PP2B are investigated and shown to mediate A1 receptor-mediated GluA1 internalization in hypoxic conditions in the rat hippocampus. Further experiments demonstrate the role of adenosine A2A receptors in potentiating hippocampal synaptic transmission in reperfusion by increasing GluA1 surface expression through increased phosphorylation of regulatory C-terminal phosphorylation sites of GluA1. The mechanism of extracellular adenosine regulation by equilibrative nucleoside transporters (ENTs) and casein kinase 2 (CK2) are examined and shown to interact in hypoxia/reperfusion experiments on hippocampal slices. Finally, using a pial vessel disruption (PVD) permanent focal cortical ischemia stroke model, experiments demonstrate increased adenosine tone in the hippocampus, which mediates increased adenosine-induced synaptic depression. CK2 inhibition was also neuroprotective after 20min hypoxia. This shows that adenosine tone is increased in the hippocampus after a small cortical stroke, implying a potential global effect of focal ischemia. Together, these studies further reveal the paramount role of adenosine as a neuromodulator in the hippocampus during neuronal insults, furthering our understanding of the mechanism of neuronal death in hypoxic and ischemic conditions.The role of adenosine as an endogenous neuromodulator is well established, but the mechanism(s) mediating the extensive modulatory and regulatory actions of adenosine have not yet been fully elucidated. In fact, although adenosine, through activation of adenosine A1 and A2A receptors, has been demonstrated as neuroprotective or neurodegenerative, respectively, little is known about the mechanism by which adenosine mediates these actions. In the hippocampus, essential physiological processes rely on adenosine signaling, including regulation of long-term potentiation (LTP) and long-term depression (LTD). Neuromodulation by adenosine is dominantly inhibitory in the hippocampus, mediated by the abundant and high-affinity adenosine A1 receptor. In ischemia and hypoxia, A1 receptor activation induces rapid synaptic depression which is mediated by multiple signaling pathways including the induction of excitatory AMPA glutamate receptor internalization, which inhibits synaptic transmission in the hippocampus. Considerable effort has been devoted to investigating the role of adenosine in ischemic stroke, due to the fact that in cerebral ischemia or hypoxia, extracellular levels of adenosine increase dramatically. This thesis explores the functional consequences of adenosine signaling in hypoxia and ischemia, which mediate GluA1 AMPA receptor subunit internalization. Three major serine/threonine protein phosphatases (PPs), PP1, PP2A, and PP2B are investigated and shown to mediate A1 receptor-mediated GluA1 internalization in hypoxic conditions in the rat hippocampus. Further experiments demonstrate the role of adenosine A2A receptors in potentiating hippocampal synaptic transmission in reperfusion by increasing GluA1 surface expression through increased phosphorylation of regulatory C-terminal phosphorylation sites of GluA1. The mechanism of extracellular adenosine regulation by equilibrative nucleoside transporters (ENTs) and casein kinase 2 (CK2) are examined and shown to interact in hypoxia/reperfusion experiments on hippocampal slices. Finally, using a pial vessel disruption (PVD) permanent focal cortical ischemia stroke model, experiments demonstrate increased adenosine tone in the hippocampus, which mediates increased adenosine-induced synaptic depression. CK2 inhibition was also neuroprotective after 20min hypoxia. This shows that adenosine tone is increased in the hippocampus after a small cortical stroke, implying a potential global effect of focal ischemia. Together, these studies further reveal the paramount role of adenosine as a neuromodulator in the hippocampus during neuronal insults, furthering our understanding of the mechanism of neuronal death in hypoxic and ischemic conditions.

Thesis (Ph.D. in Neuroscience) -- University of Colorado, 2005. / Typescript. Includes bibliographical references (leaves 116-128). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;

Thesis (Ph.D.)--University of Toledo, 2007. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Major advisor: Elizabeth Tietz. Includes abstract. Title from title page of PDF document. Bibliography: pages 88-94, 130-136, 178-189, 218-266.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Made available in DSpace on 2015-12-06T23:45:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2012 / Diversos estudos mostram que a falta de sono interfere na formacao de novas memorias, especialmente as dependentes do hipocampo. Em consonancia, ha trabalhos que mostram que a privacao de sono (PS) interfere sobre o ritmo teta hipocampal (4 a 12 Hz), mas nao ha dados consistentes sobre seus efeitos durante a aprendizagem de tarefas de memora. Ha evidencias indiretas que sugerem o envolvimento de receptores glutamatergicos ionotropicos do tipo AMPA, que constituem um fator essencial tanto para a aprendizagem de tarefas como para a plasticidade hipocampal. Tratamentos com farmacos que atuam sobre os receptores AMPA tem se mostrado eficazes na prevencao de prejuizos de memoria induzidos por patologias neurais, bem como na modulacao do ritmo teta hipocampal. Portanto, o objetivo do presente estudo foi investigar o envolvimento dos receptores AMPA hipocampais sobre os prejuizos de memoria de ratos, induzidos pela privacao de sono. Na primeira etapa, foram realizadas analises da marcacao autorradiografica de receptores AMPA e da transcricao da subunidade GluR1 apos a privacao de sono, bem como experimentos farmacologicos com potenciador (aniracetam) e antagonista (GYKI 52466) de receptores AMPA, com o proposito de prevenir os prejuizos apresentados por ratos privados de sono na tarefa de esquiva inibitoria. Na segunda etapa, foi realizada a caracterizacao do ritmo teta hipocampal e seus subtitpos (teta tipo 1 e tipo 2) durante uma tarefa de reconhecimento de objetos em apos PS. Na primeira etapa, foi observado uma diminuicao da marcacao autorradiografica de receptores AMPA especificamente na formacao hipocampal de ratos privados de sono por 96 h, que se normaliza com uma recuperacao de sono por 24 h. Por outro lado, nao foram encontradas alteracoes na hibridizacao in situ da subunidade GluR1 hipocampal. Dados de experimentos farmacologicos mostraram que a administracao aguda de aniracetam (100 mg/kg) foi eficaz na prevencao de prejuizo de desempenho de esquiva inibitoria de ratos privados de sono, ao passo que tratamentos agudo e cronico com GYKI 52466 nao surtiram efeito. Na segunda etapa, ratos com implantes de eletrodos na formacao hipocampal desempenharam uma tarefa de reconhecimento de objetos apos PS de 72 h, e apresentaram prejuizo nessa condicao. A analise da potencia do ritmo teta hipocampal mostrou que o ritmo teta tipo 2 esta reduzido durante o treino da tarefa, e que se normaliza na ocorrencia do teste apos a recuperacao de sono. A partir dos dados obtidos nas duas etapas, conclui-se que: 1) a privacao de sono reduz a marcacao de receptores AMPA hipocampais, por meio de modificacoes pos-transcricionais de suas subunidades, e que a recuperacao de sono normaliza esse efeito; 2) o potenciador aniracetam previne o prejuizo de memoria de ratos privados de sono na tarefa de esquiva inibitoria; 3) a privacao de sono modifica o ritmo teta hipocampal durante a aprendizagem de uma tarefa de reconhecimento de objetos, e sugere a participacao dos receptores AMPA hipocampais nessa condicao / BV UNIFESP: Teses e dissertações

The IEM 1460 is a potential age-specific anticonvulsant and an indicator of the distribution of AMPA receptor subtypes among rat brain cells. It is a derivative of adamantane, that was tested in previous studies on models of human myoclonic and generalized tonic-clonic seizures with promising results. In this thesis we evaluated its effect on the motor activity of rat offspring in the age of 12, 18 and 25 days, we used 90 animals in total . The effect was evaluated 30 minutes after intraperitoneal administration of IEM 1460 in two doses, 10 mg/kg or 20 mg/kg, and was compared to the control animals with physiological solution applied intraperitoneally in amount of 20 mg/kg. To test the animals we used Open field test, righting reflex, negative geotaxis, horizontal bar test, rope climbing test, regular and irregular horizontal ladder test. The tests were applied to animals in mentioned order. There were found significant changes influencing motor behaviour, primarily in the 12 days old animals with the dose of 20 mg/kg IEM 1460 and in the 25 days old animals with both doses of IEM 1460, 10 and 20 mg/kg. In the 18 days old animals the results were less significant. Powered by TCPDF (www.tcpdf.org)

by Cheng Wai Ming. / Thesis submitted in: October, 1998. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (leaves 54-68 (2nd gp.)). / Abstracts in English and Chinese. / ACKNOWLEDGEMENTS --- p.iv / ABSTRACT --- p.v / ABSTRACT (Chinese) --- p.vii / Chapter CHAPTER 1 --- LITERATURE REVIEW --- p.1 / Chapter 1.1 --- Ionotropic glutamate receptors --- p.1 / Chapter 1.1.1 --- AMP A receptor --- p.3 / Chapter 1.1.1.1 --- Structure of AMP A receptor --- p.3 / Chapter 1.1.1.2 --- Electrophysiological properties of AMPA receptor --- p.4 / Chapter 1.1.1.3 --- Pharmacology of AMPA receptors --- p.6 / Chapter 1.1.1.4 --- Kinetics of AMPA receptors --- p.8 / Chapter 1.1.2 --- NMDA receptor --- p.9 / Chapter 1.1.2.1 --- Structure of NMDA receptor --- p.9 / Chapter 1.1.2.2 --- Electrophysiological properties of NMDA receptor --- p.10 / Chapter 1.1.2.3 --- Pharmacology of NMDA receptor --- p.11 / Chapter 1.1.2.4 --- Kinetics of NMDA receptor --- p.12 / Chapter 1.2. --- The basal ganglia and the SNR --- p.12 / Chapter 1.3 --- Excitatory glutamatergic inputs on SNR --- p.16 / Chapter 1.4 --- Aim of study --- p.17 / Chapter CHAPTER 2 --- Electrophysiological properties of SNR neurones --- p.18 / Chapter 2.1 --- Introduction --- p.18 / Chapter 2.2 --- Methods --- p.19 / Chapter 2.2.1 --- In vitro slice preparation and maintenance --- p.19 / Chapter 2.2.2 --- Whole-cell patch-clamp recording --- p.20 / Chapter 2.2.3 --- Solutions and drugs --- p.21 / Chapter 2.2.4 --- Histological methods --- p.21 / Chapter 2.2.5 --- Data analysis --- p.22 / Chapter 2.3 --- Results --- p.22 / Chapter 2.3.1 --- Passive membrane properties of SNR neurones --- p.22 / Chapter 2.3.2 --- Firing rate and action potential characteristics --- p.23 / Chapter 2.3.3 --- Firing patterns --- p.23 / Chapter 2.3.4 --- Weak hyperpolarization activated inward rectification --- p.24 / Chapter 2.3.5 --- Slow aflerhyperpolarization --- p.25 / Chapter 2.3.6 --- Current-frequency relationship --- p.25 / Chapter 2.3.7 --- Morphology of labelled SNR neurones --- p.25 / Chapter 2.4 --- Discussion and conclusion --- p.26 / Chapter CHAPTER 3 --- AMPA and NMDA induced membrane responses --- p.30 / Chapter 3.1 --- Introduction --- p.30 / Chapter 3.2 --- Methods --- p.31 / Chapter 3.2.1 --- In vitro slice preparation and maintenance --- p.31 / Chapter 3.2.2 --- Whole-cell patch-clamp recording --- p.31 / Chapter 3.2.3 --- Solutions and drugs --- p.31 / Chapter 3.2.4 --- Drug application --- p.32 / Chapter 3.2.5 --- Immunocytochemistry --- p.32 / Chapter 3.2.6 --- Data analysis --- p.33 / Chapter 3.3 --- Results --- p.33 / Chapter 3.3.1 --- AMPA induced responses in SNR GABA neurones --- p.33 / Chapter 3.3.1.1 --- AMPA induced membrane depolarization --- p.33 / Chapter 3.3.1.2 --- AMPA induced membrane current --- p.34 / Chapter 3.3.1.3 --- Current-voltage relationship --- p.34 / Chapter 3.3.1.4 --- Effect of NBQX --- p.35 / Chapter 3.3.1.5 --- Effects of JSTX and spermine --- p.35 / Chapter 3.3.2 --- NMDA-induced response in SNR GABA neurones --- p.36 / Chapter 3.3.2.1 --- NMDA induced membrane depolarization --- p.36 / Chapter 3.3.2.2 --- NMDA induced membrane current --- p.36 / Chapter 3.3.2.3 --- APV blocked NMDA-induced current --- p.36 / Chapter 3.3.2.4 --- Effect of glycine on NMDA induced response --- p.37 / Chapter 3.3.2.5 --- Mg2+-sensitivity --- p.37 / Chapter 3.3.2.6 --- Current-voltage relationship --- p.38 / Chapter 3.3.3 --- GluR2 subunit immunostaining --- p.38 / Chapter 3.4 --- Discussion and conclusion --- p.39 / Chapter 3.4.1 --- AMPA receptors in SNR neurones --- p.39 / Chapter 3.4.2 --- NMDA receptors in SNR neurones --- p.41 / Chapter 3.4.3 --- Functional significance --- p.41 / Chapter CHAPTER 4 --- Glutamate-mediated synaptic currents in SNR --- p.43 / Chapter 4.1 --- Introduction --- p.43 / Chapter 4.2 --- Methods --- p.44 / Chapter 4.2.1 --- In vitro slice preparation and maintenance --- p.44 / Chapter 4.2.2 --- Electrophysiological recordings --- p.44 / Chapter 4.2.3 --- Electrical stimulation --- p.45 / Chapter 4.2.4 --- Solutions and drugs --- p.45 / Chapter 4.2.5 --- Data analysis --- p.46 / Chapter 4.3 --- Results --- p.46 / Chapter 4.3.1 --- Characteristics of spontaneous EPSCs --- p.46 / Chapter 4.3.1.1 --- General characteristics --- p.46 / Chapter 4.3.1.2 --- Kinetics --- p.47 / Chapter 4.3.1.3 --- Pharmacology --- p.47 / Chapter 4.3.2 --- Characteristics of evoked EPSCs --- p.48 / Chapter 4.3.2.1 --- General characteristics --- p.48 / Chapter 4.3.2.2 --- Pharmacological characterization --- p.49 / Chapter 4.3.2.3 --- Effects of bicuculline --- p.50 / Chapter 4.4 --- Discussion and conclusion --- p.50 / Chapter 4.4.1 --- Excitatory transmission onto SNR neurones --- p.50 / Chapter 4.4.2 --- Source of excitatory drive --- p.51 / Chapter 4.4.3 --- Interaction with GABA inputs --- p.52 / Chapter 4.4.4 --- Functional significance --- p.52 / REFERENCES --- p.54

Ho, Tsz Wan. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 125-165). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Thesis (Ph.D. in Pharmacology) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 132-151). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Thesis (Ph.D. in Pharmacology) -- University of Colorado Denver, 2008. / Typescript. Includes bibliographical references (leaves 100-118).