Previously we reported that transgenic rats overexpressing mutant human APP (McGill-R-Thy1-APP) develop an Aß-dependent deficit in long-term potentiation (LTP) long before the deposition of plaques1. Since acute Aß oligomer-cellular prion protein (PrP) interaction can disrupt synaptic plasticity via metabotropic glutamate 5 (mGlu5) receptors 2,3we investigated if these mechanisms mediated the disruption of synaptic plasticity in the chronic rat model. We recorded field potentials from CA3-to-CA1 synapses in the dorsal hippocampus of chronically implanted 5-month-old freely behaving male McGill-R-Thy1-APP rats. A cannula was implanted in the lateral ventricle at the same time as electrodes under recovery anaesthesia (ketamine, 80 mg/kg and xylazine, 8 mg/kg, both i.p.). Our standard 200 Hz high frequency stimulation (HFS) protocol was used to induce LTP. Values are mean ± SEM % baseline at 3 h post-HFS and compared by paired or unpaired Student’s t-tests. LTP was completely inhibited in these pre-plaque transgenic rats (101.3±4.4%, n=10, p>0.05, compared with pre-HFS baseline; p<0.05 compared with wild-type littermates, 136.6±4.8%, n=6). Repeated intracerebroventricular injection of a monoclonal antibody that prevents Aß oligomer-binding to PrP, ICSM35 (5 injections of 60 µg, over 3 days), reversed the LTP deficit (131.0±5.6%, n=5, p<0.05 Vs. 104.4±7.2%, in 6 animals treated with an isotype control antibody, Bric126). Notably, a highly sensitive anti-Aß oligomer immunoassay revealed that detectable amounts of soluble Aß aggregates began to appear in the brains of transgenic rats around 5 months of age. Moreover, repeated intraperitoneal injection of the metabotropic glutamate 5 (mGlu5) receptor antagonist CTEP (two injections of 2mg/kg over 3 days) also significantly reduced the LTP deficit (118.0±2.2%, n=5, P<0.05 Vs. 100.7±1.6% in the same animals before starting treatment). These findings strongly indicate that the LTP inhibition in this transgenic rat model requires cellular prion protein and mGlu5 receptors.