Amyloid β-protein differentially affects NMDA receptor- and GABAA receptor-mediated currents in rat hippocampal CA1 neurons

Although the aggregated amyloid beta-protein (A beta) in senile plaques is one of the key neuropathological features of Alzheimer's disease (AD), soluble forms of A beta also interfere with synaptic plasticity at the early stage of AD. The suppressive action of acute application of A beta on hippocampal long-term potentiation (LTP) has been reported widely, whereas the mechanism underlying the effects of Ab is still mostly unknown. The present study, using the whole-cell patch clamp technique, investigated the effects of A beta fragments (A beta(25-35) and A beta(31-35)) on the LTP induction-related postsynaptic ligand-gated channel currents in isolated hippocampal CA1 neurons. The results showed a rapid but opposite action of both peptides on excitatory and inhibitory receptor currents. Glutamate application-induced currents were suppressed by A beta(25-35) in a dose-dependent manner, and further N-methyl-D-aspartate(NMDA) receptor-mediated currents were selectively inhibited. In contrast, pretreatment with A beta fragments potentiated gamma-aminobutyric acid (GABA)-induced whole-cell currents. As a control, A beta(35-31), the reversed sequence of A beta(31-35), showed no effect on the currents induced by glutamate, NMDA or GABA. These results may partly explain the impaired effects of A beta on hippocampal LTP, and suggest that the functional down-regulation of NMDA receptors and up-regulation of GABA(A) receptors may play an important role in remodeling the hippocampal synaptic plasticity in early AD. (C) 2009 National Natural Science Foundation of China and Chinese Academy of Sciences. Published by Elsevier Limited and Science in China Press. All rights reserved.