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The Journal of Neuroscience, December 15, 1999, 19(24):10977-10984
Upregulation of GABA Neurotransmission Suppresses Hippocampal
Excitability and Prevents Long-Term Potentiation in Transgenic
Superoxide Dismutase-Overexpressing Mice
Y.
Levkovitz1,
E.
Avignone1,
Y.
Groner2, and
M.
Segal1
Departments of 1 Neurobiology and
2 Molecular Genetics, The Weizmann Institute, Rehovot
76100, Israel
Cu/Zn superoxide dismutase (SOD-1) is a key enzyme in oxygen
metabolism in the brain. Overexpression of SOD-1 in transgenic (Tg)
mice has been used to study the functional roles of this enzyme in
oxidative stress, lipid peroxidation, and neurotoxicity. We found that
Tg-SOD-1 mice are strikingly less sensitive to kainic acid-induced behavioral seizures than control mice. Furthermore, the hippocampus of Tg-SOD-1 mice was far less sensitive to local application of bicuculline, a GABA-A antagonist, than the hippocampus of control mice. GABAergic functions, expressed in extracellular paired-pulse depression, and in IPSCs recorded in dentate
granular cells were enhanced in Tg-SOD-1 mice. Finally, long-term
potentiation (LTP), not found in the dentate gyrus of Tg-SOD-1 mice,
could be restored by local blockade of inhibition and could be blocked in control mice by injection of diazepam, which amplifies inhibition. These results indicate that constitutive elevation of SOD-1 activity exerts a major effect on neuronal excitability in the hippocampus, which, in turn, controls hippocampal ability to express LTP.
Key words:
transgenic SOD-1 mice; LTP; seizure; hippocampus; IPSCs; perforant path
Copyright © 1999 Society for Neuroscience 0270-6474/99/192410977-08$05.00/0
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