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Soluble Aβ1-40 Peptide Increases Excitatory Neurotransmission and Induces Epileptiform Activity in Hippocampal Neurons

2011; IOS Press; Volume: 23; Issue: 4 Linguagem: Inglês

10.3233/jad-2011-091717

1875-8908

Magdalena E. Cuevas, Henny Haensgen, Fernando J. Sepúlveda, Gabriela Zegers, Jorge Roa, Carlos Opazo, Luis G. Aguayo,

Computational Drug Discovery Methods

It is believed that amyloid-β peptide (Aβ), in its aggregated-oligomeric state, constitutes one of the neurotoxic factors involved in the pathogenesis of Alzheimer's disease. With the objective of studying a potential role of the peptide on synaptic transmission, we studied the effect of soluble Aβ(1-40) on synaptic transmission in rat hippocampal neurons. Neurons incubated with 500 nM of Aβ(1-40) peptide for 3 days presented higher levels of intracellular calcium transients, as evaluated by fluorimetric techniques. These effects of Aβ were time and concentration dependent and were accompanied by increases in glutamatergic (0.8±0.2 Hz to 2.9±0.6 Hz), but not GABAergic, transmission. The analysis of pharmacologically isolated currents in treated neurons showed increases in both AMPA- and NMDA-mediated currents as compared to control. The effects of the peptide on the frequency of synaptic currents correlated well with increases in the number of SV2 puncta and of FM1-43 destaining, suggesting a presynaptic locus for the peptide. The data also shows that application of either Aβ or bicuculline alone for 24 h was without effects on neurotransmission. However, their co-application induced an increase in synaptic transmission which was accompanied by synchronous discharges reminiscent to those produced by pro-convulsive drugs, such as bicuculline. In conclusion, these results suggest that the soluble form of Aβ(1-40) participates in the regulation of synaptic transmission increasing excitability and producing a pre-epileptogenic state in hippocampal neurons.