α7nAchR/NMDAR coupling affects NMDAR function and object recognition

The alpha 7 nicotinic acetylcholine receptor (nAchR) and NMDA glutamate receptor (NMDAR) are both ligand-gated ion channels permeable to Ca2+ and Na+. Previous studies have demonstrated functional modulation of NMDARs by nAchRs, although the molecular mechanism remains largely unknown. We have previously reported that alpha 7nAchR forms a protein complex with the NMDAR through a protein-protein interaction. We also developed an interfering peptide that is able to disrupt the alpha 7nAchR-NMDAR complex and blocks cue-induced reinstatement of nicotine-seeking in rat models of relapse. In the present study, we investigated whether the alpha 7nAchR-NMDAR interaction is responsible for the functional modulation of NMDAR by alpha 7nAchR using both electrophysiological and behavioral tests. We have found that activation of alpha 7nAchR upregulates NMDAR-mediated whole cell currents and LTP of mEPSC in cultured hippocampal neurons, which can be abolished by the interfering peptide that disrupts the alpha 7nAchR-NMDAR interaction. Moreover, administration of the interfering peptide in mice impairs novel object recognition but not Morris water maze performance. Our results suggest that alpha 7nAchR/NMDAR coupling may selectively affect some aspects of learning and memory.