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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 Oh^{1, 2}, John M. Power¹, Lucien T. Thompson^{1, 2}, Pamela L. Moriearty³, and John F. Disterhoft^{1, 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

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Copyright © 1999 Society for Neuroscience  0270-6474/99/1951814-10$05.00/0

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