Divergent effects of Abeta1-42 on ionotropic glutamate receptor-mediated responses in CA1 neurons in vivo.
Aggregated Abeta1-42 is hypothesized to be the central cause of Alzheimer's disease. However, early changes in synaptic activity may be detected in the disease long before a significant cell loss is manifested. Despite the fact that Abeta1-42 interference with long-term potentiation (LTP) and the field excitatory postsynaptic potential (fEPSP) is well documented, the exact mechanism of these events remains to be clarified. Here we studied the effects of iontophoretically applied Abeta1-42 on the neuronal firing evoked in vivo on the CA1 hippocampal neurons of Wistar rats by different agonists of the ionotropic glutamate receptors: N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainic acid (KA). NMDA elicited firing enhanced in all of the measured cells; in contrast, the AMPA-mediated responses decreased significantly after Abeta1-42 ejection. The changes in KA-evoked responses to Abeta1-42 revealed two types of cells. In the first type, the KA-mediated firing remained at the control level, while in the second type, Abeta1-42 attenuated the KA-evoked responses. A protective pentapeptide, Leu-Pro-Tyr-Phe-Asp-amide, was used to verify the specificity of these beta-amyloid-elicited effects. The pentapeptide protected against the modulatory effects of Abeta1-42 on the NMDA and AMPA responses. In conclusion, we have shown that Abeta1-42 exerts divergent effects on the activity of the ionotropic glutamate receptors in vivo. These results suggest that the LTP disruption and fEPSP attenuation seen after Abeta1-42 application are in part due to the altered function of these receptors.
Szegedi
Viktor
V
Department of Medical Chemistry, Juhász Gyula College, University of Szeged, Dóm square 8, Szeged H-6720, Hungary. szegv@yahoo.com
Juhász
Gábor
G
Budai
Dénes
D
Penke
Botond
B
D016229:Amyloid beta-Peptides / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D006624:Hippocampus / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D010446:Peptide Fragments / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000502:physiology*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017470:Receptors, Glutamate; C075222:amyloid beta-protein (1-42)