NS6740, an α7 nicotinic acetylcholine receptor silent agonist, disrupts hippocampal synaptic plasticity

Long-term potentiation (LTP) in the dentate gyrus was previously shown to be enhanced by nicotine, an effect dependent on both homomeric alpha 7 and heteromeric alpha 2 beta 2 nicotinic acetylcholine receptors (nAChR). In our experiments, bath-applied nicotine produced no significant enhancement of LTP. The alpha 7 nAChR silent agonist NS6740, a weak activator of alpha 7 nAChR ion channels but an effective modulator of the cholinergic anti-inflammatory pathway, decreased LTP and, additionally, produced a substantial reduction in the baseline synaptic function prior to the high frequency stimulation used to induce LTP. The effects of NS6740 on the various ligand-gated ion channels associated with the generation and modulation of dentate LTP were evaluated with receptors expressed in Xenopus oocytes. A 60 s pre-application of 5 mu M NS6740 to alpha 7 receptors blocked the response to subsequent applications of acetylcholine (ACh). In contrast, the responses of alpha 2 beta 2 nAChR to control applications of ACh were not significantly affected by NS6740. Likewise, responses of cells expressing GluR1 + GluR2 AMPA-type glutamate receptor subunits or GABA(A) alpha 1, beta 2, and gamma 2L subunits to control agonist applications (100 mu M kainic acid or 10 mu M GABA, respectively), were unaffected by NS6740. The effects of NS6740 on alpha 7 were inconsistent with simple antagonism since, while unresponsive to ACh, the receptors exposed to NS6740 were effectively activated by the positive allosteric modulator PNU-120596. The results support the hypothesis that NS6740 switches the mode of alpha 7 signaling in a channel-independent manner that can reduce synaptic function.