Transgenic mice overexpressing amyloid precursor protein (APP) have previously been shown to have deficits in either hippocampal basal synaptic transmission (Fitzjohn et al. 2001) or synaptic plasticity (Chapman et al. 1999) but not both. We have studied synaptic transmission and plasticity in hippocampal slices taken from aged (12-14 months) TAS10 mice (Richardson et al. 2003) overexpressing APP harbouring the Swedish mutation (K670N and M671L), in an attempt to resolve these confounding reports. In addition, we have examined neuronal network behaviour induced by 4-aminopyridine (4-AP).

Wildtype (WT) and heterozygous transgenic mice (male and female) were killed humanely and 400 µm-thick horizontal hippocampal slices prepared in a standard manner. Data are presented as mean ± S.E.M. and statistical significance determined using Student’s unpaired t test, unless otherwise stated.

In TAS10 slices we observed a significant deficit in basal synaptic transmission in the CA3-CA1 Schaffer collateral pathway such that the mean ratio of the slope of the maximal fEPSP to fibre volley amplitude was approximately six-fold lower (0.63 ± 0.14, n = 14) than in WT slices (3.27 ± 0.55, n = 11; P < 0.001). Despite this deficit, relative levels of short-term synaptic plasticity in the CA1 region of TAS10 slices (paired pulse and multiple pulse facilitation, at frequencies of 1, 5 and 10 Hz) were normal. In addition, LTP induced by a theta burst stimulation paradigm, was normal in the CA1 of TAS10 slices (WT = 160 ± 12 % of baseline, n = 8; TAS10 = 186 ± 10 % of baseline, n = 8, P > 0.05 2-way ANOVA). The inter-event interval (IEI) of synchronous events induced by 100 µM 4-AP was significantly longer in TAS10 hippocampal slices (IEI, 6.9 ± 1.7 s; n = 8) compared with WT slices (IEI, 2.4 ± 0.6 s; n = 6, P < 0.05). Addition of NBQX (20 µM) and D-AP5 (50 µM) to the bath medium, isolated bicuculline-sensitive GABA-mediated synchronous events in both WT and TAS10 slices. These GABAergic events were similar in frequency in WT and TAS10 slices (IEI, 10.3 ± 1.2 s in WT slices cf. 10.8 ± 1.3 s in TAS10 slices), suggesting that GABAergic systems remain relatively unaffected by overproduction of β-amyloid.

This study suggests that the deficit in glutamatergic synaptic transmission, observed in several strains of APP overexpressing mice, may be coupled with alterations in synchronous network activity, which in turn may lead to deficient information processing.