The role of c-Jun N-terminal kinase in the A beta-mediated impairment of LTP and regulation of synaptic transmission in the hippocampus.
The effects of the beta-amyloid peptide (Abeta) fragment 25-35 were investigated on hippocampal synaptic transmission and long-term potentiation (LTP) in vitro. Abeta([25-35]) was found to impair both post-tetanic potentiation (PTP) and LTP in the hippocampal CA1. The anthra[1,9-cd]pyrazol-6(2H)-one, SP600125, was used to inhibit c-Jun N-terminal kinase (JNK) activity, which is believed to mediate cell death. Prior application of SP600125 attenuated the Abeta([25-35])-mediated impairment of PTP and LTP, when measured from the pre-drug baseline. In the presence of SP600125 alone, we observed an increase in baseline synaptic transmission and reduction in paired-pulse facilitation, consistent with an increase in synaptic transmission. There was no alteration in the level of PTP and LTP obtained, when measured from the pre-drug baseline. In the presence of both SP600125 and Abeta, however, PTP was greatly enhanced compared with controls. We therefore suggest that the activation of the JNK signalling pathway mediates the effects of Abeta on synaptic plasticity. Our data also indicate that endogenous JNK activity may regulate neurotransmitter release in the hippocampal CA1 in vitro.
Department of Physiology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
Derek A
DA
Costello
Caroline E
CE
Herron
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology; D048031:JNK Mitogen-Activated Protein Kinases; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D016229:Amyloid beta-Peptides; D000873:Anthracenes; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases