Galantamine increases excitability of CA1 hippocampal pyramidal neurons

Abstract

Galantamine is a third generation cholinesterase inhibitor and an allosteric potentiating ligand of nicotinic acetylcholine receptors. It enhances learning in aging rabbits and alleviates cognitive deficits observed in patients with Alzheimer’s disease. We examined galantamine’s effect on CA1 neurons from hippocampal slices of young and aging rabbits using current-clamp, intracellular recording techniques. Galantamine (10–200μM) dose-dependently reduced the postburst afterhyperpolarization and the spike-frequency accommodation of CA1 neurons from both young and aging animals. These reductions were partially, but significantly, reversed by the addition of the muscarinic receptor antagonist, atropine (1μM), to the perfusate. In contrast, the nicotinic acetylcholine receptor antagonist, α-bungarotoxin (10nM), had no effect; i.e. α-bungarotoxin did not reverse the afterhyperpolarization and accommodation reductions. The allosteric potentiating ligand effect was examined by stimulating the Schaffer collateral and measuring the excitatory postsynaptic potentials for 30 min during bath application of galantamine. Galantamine (200μM) significantly enhanced the excitatory postsynaptic potential amplitude and area over time. These effects were blocked by 10nM α-bungarotoxin, supporting a role for galantamine as an allosteric potentiating ligand. We did not observe a facilitation of the excitatory postsynaptic potentials with 1μM galantamine. However, when the excitatory postsynaptic potential was pharmacologically isolated by adding 10μM gabazine (GABAA receptor antagonist) to the perfusate, 1μM galantamine potentiated the subthreshold excitatory postsynaptic potentials into action potentials. We propose that the learning enhancement observed in aging animals and the alleviation of cognitive deficits associated with Alzheimer’s disease after galantamine treatment may in part be due to the enhanced function of both nicotinic and muscarinic excitatory transmission on hippocampal pyramidal neurons.