Alzheimer’s disease is associated with elevated levels of β-amyloid (Aβ) peptide. Long-term potentiation (LTP) is an activity-dependent increase in synaptic efficacy, used as a cellular model of learning. Post-tetanic potentiation (PTP) is a short-term enhancement in synaptic transmission due to increased neurotransmitter release. Aβ_[25-35] is known to depress LTP in the hippocampal CA1 region in vitro (Costello & Herron, 2002) while Aβ peptide also enhances the phosphorylation of JNK (Costello et al. 2002). We have investigated therefore the role of JNK in synaptic transmission and the Aβ-mediated depression of LTP. Experiments were performed on hippocampal slices (350 µm) from humanely decapitated male Wistar rats (50-100 g). Field excitatory postsynaptic potentials were recorded in the CA1 region and LTP was induced by trains of high-frequency stimuli (HFS) consisting of 10 trains of 10 pulses at 200 Hz (repeated three times at 20 s intervals) delivered to the Schaffer collateral/commissural pathway. In control slices, PTP recorded 5 min post-HFS measured 186 ± 7 % (EPSP slope ± S.E.M., n = 8) while robust LTP was recorded 60 min post-HFS (167 ± 5 %, n = 8). Application of Aβ_[25-35] (200 nM) 60 min prior to HFS reduced significantly PTP and LTP (154 ± 8 %, n = 6, P < 0.01 and 137 ± 6 %, n = 6, P < 0.005, ANOVA). Application of SP600125, 30 min pre-HFS also impaired the level of LTP at concentrations of 1 or 20 µM (142 ± 7 %, n = 5, P < 0.01 and 142 ± 4 %, n = 6, P < 0.005, respectively) compared with controls. To investigate the effects of Aβ_[25-35] when JNK was inhibited, SP600125 (1 and 20 µM) and Aβ_[25-35] (200 nM) were applied 90 and 60 min, respectively, prior to HFS. Application of SP600125 prior to Aβ_[25-35] did not alter significantly the impairment of LTP produced by either agent alone (133 ± 6% 1 µM SP600125+Aβ, n = 5 and 142 ± 6 %, 20 µM SP600125+Aβ, n = 6). Treatment with Aβ following prior application of 20 µM SP600125 reversed significantly the depression in PTP (186 ± 5 %, n = 6, P < 0.005) compared with Aβ alone. Baseline synaptic transmission was increased significantly following the application of 20 µM SP600125 (116 ± 4 %, n = 6, P < 0.005) accompanied by a reduction in paired pulse facilitation (inter-pulse interval 50 ms) (1.26 ± 0.06, n = 6, P < 0.05, unpaired t test) compared with controls (1.42 ± 0.03, n = 6). These results suggest that JNK is unlikely to be involved in the Aβ-mediated impairment of LTP. JNK may, however, play a direct role in neurotransmitter release and synaptic plasticity.

This work was supported by the Health Research Board of Ireland and Enterprise Ireland.