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mco1251386977.pdf (892.24 KB)
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Regulation of GABA(A) receptor function by hypoxia in rat primary cortical neurons
Author Info
Wang, Liping
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=mco1251386977
Abstract Details
Year and Degree
2009, Doctor of Philosophy in Biomedical Sciences (Ph.D.), University of Toledo, College of Medicine.
Abstract
Fast inhibitory synaptic transmission is mainly mediated by GABAA receptors (GABAARs), a key determinant of neuronal excitability in the central nervous system. Modulation of GABAAR expression and function has important consequences to control neural activity at both cell and network levels. GABAARs are clinically important targets for a number of anti-convulsant, anxiolytic and sedative-hypnotic agents and are implicated in several prominent neurological and mental disorders including epilepsy, anxiety, cognitive deficits, schizophrenia, depression and drug abuse. In this dissertation, we investigated the effects of hypoxia on GABAAR function in rat primary cortical neurons. Maximal GABA currents were significantly reduced immediately following 4 h hypoxia and after 48 h recovery without a change in the EC50 for GABA. 2 h or 8 h hypoxic exposure did not cause significant effects on GABA currents. 4 h hypoxia also affected GABAAR benzodiazepine pharmacology. Maximal potentiation of GABA currents by diazepam increased immediately following 4 h hypoxia, while zolpidem enhancement of GABA currents increased after 48 h recovery. Hypoxic exposure resulted in a depolarizing shift in the equilibrium potential for chloride at 24 h recovery after 4 h hypoxia. The L-type voltage-gated calcium channel (L-VGCC) antagonist, nitrendipine, during hypoxia or control treatment, not only prevented the reduction of GABA currents after hypoxia, but also increased the control currents over baseline. Nitrendipine also prevented the increase in zolpidem potentiation of GABA currents after 48 h recovery and the depolarizing shift in chloride reversal potential. These data demonstrated that the effects of hypoxia on GABA currents, zolpidem pharmacology and chloride reversalpotential require L-VGCC activation. Calcium entry through L-VGCC activated the calcium/calmodulin-dependent phosphatase, calcineurin (CaN). Inhibition of CaN activity acutely reversed the reduction of GABA currents immediately following 4 h hypoxia, but not at 48 h recovery. Both basal and maximal CaN activity were unchanged at each recovery time after 4 h hypoxia. These data suggest that CaN regulates GABAAR function at the early recovery time and that later changes in GABAAR function might involve separate mechanisms. Understanding the mechanisms underlying calciumdependent modulation of GABAAR function after hypoxia may provide new insights into treatment of hypoxia-induced seizures and other neurological disorders associated with GABAAR dysfunction.
Committee
L. John Greenfield, M.D., Ph.D. (Committee Chair)
Elizabeth Tietz, Ph.D. (Committee Member)
David Giovannucci, Ph.D. (Committee Member)
Linda Dokas, Ph.D. (Committee Member)
Zi-Jian Xie, Ph.D. (Committee Member)
Pages
156 p.
Subject Headings
Neurology
;
Physiological Psychology
Keywords
hypoxia
;
GABA(A) reception
;
primary cortical neurons
;
patch clamp recording
;
gramicidin
;
benzodiazepines
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Citations
Wang, L. (2009).
Regulation of GABA(A) receptor function by hypoxia in rat primary cortical neurons
[Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1251386977
APA Style (7th edition)
Wang, Liping.
Regulation of GABA(A) receptor function by hypoxia in rat primary cortical neurons.
2009. University of Toledo, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=mco1251386977.
MLA Style (8th edition)
Wang, Liping. "Regulation of GABA(A) receptor function by hypoxia in rat primary cortical neurons." Doctoral dissertation, University of Toledo, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=mco1251386977
Chicago Manual of Style (17th edition)
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Document number:
mco1251386977
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Copyright Info
© 2009, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.