Nicotinic acetylcholine receptors contribute to learning-induced metaplasticity in the hippocampus

Abstract

Hippocampal learning is thought to induce metaplasticity that can facilitate subsequent learning. Administered at single low doses, the N-methyl-D-aspartate-type glutamate receptor (NMDAR) antagonist memantine predominantly blocks α7 nicotinic acetylcholine receptors (α7 nAChRs). We hypothesized that if α7 nAChRs contribute to learning-induced metaplasticity in the hippocampus, blockade of these receptors with low-dose memantine would selectively interfere with a facilitation of subsequent learning without impairing hippocampal learning per se. To test this hypothesis, we devised a randomized controlled trial (RCT), in which healthy volunteers were administered a 20-mg single oral dose of memantine (MEM) or placebo (PLC) and underwent functional MRI (fMRI) during three subsequent runs of a hippocampal learning task. We found no discrepancies in behavioral learning between MEM- and PLC-treated subjects in the first and second run of the task. In the third run, however, only the PLC-treated group showed facilitated behavioral learning, an effect paralleled by decreased neural responses in the hippocampal cornu ammonis (CA) region. Our findings suggest that blockade of α7 nAChRs selectively interfered with a learning-induced facilitation of subsequent learning, while leaving unimpaired hippocampal learning per se. Our results provide support for a relevant contribution of α7 nAChRs to learning-associated metaplasticity in the hippocampus. This study was supported by DFG (HU1302/2 – 2), MIWFT NRW (NEMO – Neuromodulation of Emotion).