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      Adenosine Signalling and Regulation of Ca2+-permeable AMPA Receptors in Hypoxia

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      QIN-THESIS-2018.pdf (3.135Mb)
      Date
      2018-05-01
      Author
      Qin, Xin 1992-
      Type
      Thesis
      Degree Level
      Masters
      Metadata
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      Abstract
      Stroke is one of major causes of death, and ischemic stroke attributes to approximately 87% of all strokes. Our lab has previously shown that during an ischemic insult, adenosine A1 receptor (A1R) activation in the rat hippocampus leads to AMPA receptor (AMPAR) downregulation and persistent synaptic inhibition. This persistent synaptic depression could contribute to neuronal damage, as neurons require constant excitatory inputs. Moreover, we observed an adenosine-induced post-hypoxia synaptic potentiation (APSP) in rat hippocampal CA1 field potential recordings. Hypoxia-induced cell death and APSP were significantly reduced when rat hippocampal slices were pretreated with either A1R or A2AR antagonist, indicating a potential interaction between A1Rs and A2ARs through yet unknown mechanisms. This study further explores the role of glutamate receptors in the generation of APSP through adenosine signalling. We hypothesize that hypoxia induces A1R-mediated, dynamin (a GTPase regulating endocytosis)-dependent internalization of A1Rs and GluA2/GluA1 AMPARs, which is then followed by an A2AR-mediated upregulation of these AMPARs, which is a prerequisite for full expression of APSP. Electrophysiology studies demonstrated that synaptic transmissions and APSPs in the rat hippocampal CA1 region are mostly mediated by AMPAergic mechanisms, instead of NMDA receptors, and that these required both A1R and A2AR signalling cross-talk. To determine whether Ca2+-permeable AMPARs (CP-AMPARs) underlie APSP, I performed experiments to test the effects of selective CP-AMPAR antagonists on APSP levels, including NASPM, IEM 1460 and Philanthotoxin-74. Application of the CP-AMPARs antagonists at the early phase of hypoxic stimulation blocked the generation of APSPs, whereas no attenuated effects were observed when applied after the expression of APSPs. In contrast, the clinically approved anti-seizure drug Perampanel, which is a non-competitive AMPAR antagonist, blocked the generation of APSP. Surprisingly, all CP-AMPAR antagonists tested were effective in preventing hypoxia-induced hippocampal neuronal damage during the early phase of hypoxic stimulation, but Perampanel was the only compound that prevented neuronal damage during normoxic brain slice reperfusion. Additional studies of leukocyte-specific protein1 (LSP1) knockout mice also revealed a potential contribution of LSP1 to altering synaptic plasticity during hypoxia-reperfusion injury models. In particular, LSP1 may regulate the levels of synaptic depression and CP-AMPARs during A1R stimulation in hypoxic conditions. Collectively, this study has provided further evidence for CP-AMPARs’ role in delayed hippocampal injury, which involves both A1Rs and A2ARs, and reveals GluA2-lacking AMPARs as a potential target for designing neuroprotective drugs in the late stage neurodegeneration related to hypoxia/ischemia.
      Degree
      Master of Science (M.Sc.)
      Department
      Medicine
      Program
      Health Sciences
      Supervisor
      Cayabyab, Francisco
      Committee
      Campanucci, Veronica; Laprairie, Robert; Taghibiglou, Changiz; Walz, Wolfgang
      Copyright Date
      October 2018
      URI
      http://hdl.handle.net/10388/8548
      Subject
      Adenosine, Stroke, Hypoxia
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      • Graduate Theses and Dissertations
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