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Metrifonate decreases sI(AHP) in CA1 pyramidal neurons in vitro
J M Power1, M M Oh, J F Disterhoft
1Department of Cell and Molecular Biology, Northwestern University, Chicago, Illinois 60611-3008, USA.
Abstract:
Metrifonate, a cholinesterase inhibitor, has been shown to enhance learning in aging rabbits and rats, and to alleviate the cognitive deficits observed in Alzheimer's disease patients. We have previously determined that bath application of metrifonate reduces the spike frequency adaptation and postburst afterhyperpolarization (AHP) in rabbit CA1 pyramidal neurons in vitro using sharp electrode current-clamp recording. The postburst AHP and accommodation observed in current clamp are the result of four slow outward potassium currents (sI(AHP), I(AHP), I(M), and I(C)) and the hyperpolarization activated mixed cation current, I(h). We recorded from visually identified CA1 hippocampal pyramidal neurons in vitro using whole cell voltage-clamp technique to better isolate and characterize which component currents of the AHP are affected by metrifonate. We observed an age-related enhancement of the slow component of the AHP tail current (sI(AHP)), but not of the fast decaying component of the AHP tail current (I(AHP), I(M), and I(C)). Bath perfusion of metrifonate reduced sI(AHP) at concentrations that cause a reduction of the AHP and accommodation in current-clamp recordings, with no apparent reduction of I(AHP), I(M), and I(C). The functional consequences of metrifonate administration are apparently mediated solely through modulation of the sI(AHP).
Insights
Metrifonate, a cholinesterase inhibitor, improves learning and memory by modulating the slow component of the afterhyperpolarization (sI(AHP)) in hippocampal neurons. This specific action underlies its potential therapeutic effects for cognitive decline.
Area of Science:
- Neuroscience
- Pharmacology
- Cellular Electrophysiology
Background:
- Metrifonate (cholinesterase inhibitor) enhances learning and alleviates cognitive deficits in Alzheimer's disease.
- Previous studies showed metrifonate reduces spike frequency adaptation and afterhyperpolarization (AHP) in rabbit CA1 pyramidal neurons.
- AHP and accommodation result from multiple potassium currents (sI(AHP), I(AHP), I(M), I(C)) and the I(h) current.
Purpose of the Study:
- To isolate and characterize which specific AHP component currents are affected by metrifonate.
- To investigate the cellular mechanisms underlying metrifonate's effects on neuronal excitability.
Main Methods:
- Whole-cell voltage-clamp recordings from visually identified CA1 hippocampal pyramidal neurons in vitro.
- Characterization of AHP tail currents and their components (sI(AHP), I(AHP), I(M), I(C)).
- Application of metrifonate via bath perfusion to assess its effects on isolated currents.
Main Results:
- An age-related enhancement of the slow component of the AHP tail current (sI(AHP)) was observed.
- Metrifonate selectively reduced sI(AHP) at concentrations that reduced AHP and accommodation.
- Fast decaying AHP components (I(AHP), I(M), I(C)) were not significantly affected by metrifonate.
Conclusions:
- Metrifonate's functional consequences on neuronal excitability are mediated solely through modulation of the slow component of the afterhyperpolarization (sI(AHP)).
- This selective modulation of sI(AHP) provides a cellular mechanism for metrifonate's cognitive-enhancing effects.
