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The Journal of Neuroscience, March 1, 1999, 19(5):1814-1823
Metrifonate Increases Neuronal Excitability in CA1 Pyramidal Neurons from Both Young and Aging Rabbit Hippocampus
M. Matthew Oh1, 2, John M. Power1, Lucien T. Thompson1, 2, Pamela L. Moriearty3, and John F. Disterhoft1, 2 1 Department of Cell and Molecular Biology and 2 Institute for Neuroscience, Northwestern University Medical School, Chicago, Illinois 60611-3008, and 3 Department of Psychiatry, Southern Illinois University Medical School, Springfield, Illinois 62794
The effects of metrifonate, a second generation cholinesterase inhibitor, were examined on CA1 pyramidal neurons from hippocampal slices of young and aging rabbits using current-clamp, intracellular recording techniques. Bath perfusion of metrifonate (10-200 µM) dose-dependently decreased both postburst afterhyperpolarization (AHP) and spike frequency adaptation (accommodation) in neurons from young and aging rabbits (AHP: p < 0.002, young; p < 0.050, aging; accommodation: p < 0.024, young; p < 0.001, aging). These reductions were mediated by muscarinic cholinergic transmission, because they were blocked by addition of atropine (1 µM) to the perfusate. The effects of chronic metrifonate treatment (12 mg/kg for 3 weeks) on CA1 neurons of aging rabbits were also examined ex vivo. Neurons from aging rabbits chronically treated with metrifonate had significantly reduced spike frequency accommodation, compared with vehicle-treated rabbits. Chronic metrifonate treatment did not result in a desensitization to metrifonate ex vivo, because bath perfusion of metrifonate (50 µM) significantly decreased the AHP and accommodation in neurons from both chronically metrifonate- and vehicle-treated aging rabbits. We propose that the facilitating effect of chronic metrifonate treatment on acquisition of hippocampus-dependent tasks such as trace eyeblink conditioning by aging subjects may be caused by this increased excitability of CA1 pyramidal neurons.
Key words: afterhyperpolarization; aging; atropine; carbachol; cholinesterase inhibitor; eserine; hippocampal slice; metrifonate; rabbits; spike frequency adaptation
Copyright © 1999 Society for Neuroscience 0270-6474/99/1951814-10$05.00/0
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