Cu/Zn-SOD TRANSGENIC MICE ARE IMPAIRED IN SLOW
ONSET, LONG-TERM POTENTIATION
A.R. Koudinov1,2 , Y. Groner1 and M. Segal1
1. Weizmann Institute of Science, Department of Neurobiology, Rehovot 76100, Israel
2. Russian Academy of Medical Sciences, National Mental Health Research Center, Institute of Biomedical Chemistry, Timoshenko 38-27, Moscow 121359, Russian Federation
We have previously reported that transgenic mice (TG) expressing human Cu/Zn-Superoxide Dismutase (SOD), and thus modeling chronic oxidative stress, have cognitive behavioral deficits and do not maintain tetanic long term potentiation (LTP) in the CA1 area of the hippocampus (Eur J Neurosci [1998] 10, 538-544). The aim of the present study was to elucidate the mechanisms of the TG neuronal plasticity deficit. To this end N-methyl-D-aspartate (NMDA-) LTP and non-NMDA (NN-) LTP were studied in both TG and corresponding control mouse hippocampal slices using extracellular recording of CA1 excitatory postsynaptic potentials (EPSPs), and the data were expressed as a normalized EPSP slope vs. time. NN- and NMDA-LTP were pharmacologically isolated by using specific tetanic stimulation paradigm in the presence of 25 mM D,L-2-amino-5- phosphonovaleric acid, an NMDA antagonist, and 30 mM nifedepine, a blocker of voltage-gated calcium channels, respectively (J Neurosci [1997] 17, 8695-8701). We also studied muscarinic (m-) LTP (J Neurophys [1994] 72, 2034-2040) evoked by application of 0.5 mM carbachol in the presence of 100 U/ml catalase. TG mice expressed normal NMDA-LTP which was similar to controls. In contrast, the other two types of LTP, NN-LTP and m-LTP (having similar slow onset in the control mice, 35-40 % above the baseline), did not develop in the TG slices in our experimental conditions. These observations suggest that overexpression of human Cu/Zn-SOD in mice (a situation which resembles that in Down syndrome and Alzheimer's disease) causes an impairment of slow onset LTP. This implies i) an importance of oxidative cascade reactions in generation and maintenancethe of LTP, and ii) a possible common mechanism for NN- and m-LTP.
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