Abstract
The effects of S 24795, a newly developed partial agonist at alpha7 nAChRs, were tested on synaptic transmission and plasticity using extracellular field excitatory postsynaptic potentials (fEPSPs) evoked in the CA1 region by Schaffer collateral stimulation in hippocampal slices obtained from adult mice. S 24795 reduced the amplitude of the fEPSPs in a concentration-dependent manner with an IC(50) of 127 microM and a Hill coefficient of 1.1. The reduction in amplitude of the fEPSPs started at S 24795 concentrations higher than 3muM and reached 71% of controls at 300 microM. This effect was mediated by alpha7 nAChRs since it was blocked by nAChR antagonists and was not observed in alpha7 -/- mice. This effect was probably due to a reduction in glutamate release from presynaptic terminals since it was associated with a significant increase in the paired pulse ratio. In addition, S 24795 (100 microM) significantly reduced the frequency, but not the amplitude of spontaneous excitatory postsynaptic currents, recorded in the whole cell configuration of the patch clamp technique (in voltage clamp mode), further supporting a presynaptic site of action of S 24795. In addition, S 24795 at 3 microM, a concentration that did not affect basic synaptic transmission, potentiated LTP. This effect was mediated by alpha7 nAChRs since it was prevented by MLA (10 nM) and was absent in alpha7 -/- mice. Galantamine an allosteric modulator of nAChRs, at the concentrations of 0.3-3 microM, failed to potentiate LTP. In view of its powerful effect on LTP and on cognitive function, S 24795 can be considered a novel useful tool for the treatment of AD patients and other senile forms of dementia.