Multiple effects of ß-amyloid on single excitatory synaptic connections in the PFC.

ABSTRACT

Prefrontal cortex (PFC) is recognized as an AD-vulnerable region responsible for defects in cognitive functioning. Pyramidal cell (PC) connections are typically facilitating (F) or depressing (D) in PFC. Excitatory post-synaptic potentials (EPSPs) were recorded using patch-clamp from single connections in PFC slices of rats and ferrets in the presence of ß-amyloid (Aß). Synaptic transmission was significantly enhanced or reduced depending on their intrinsic type (facilitating or depressing), Aß species (Aß 40 or Aß 42) and concentration (1-200 nM vs. 0.3-1 µ M). Nanomolar Aß 40 and Aß 42 had opposite effects on F-connections, resulting in fewer or increased EPSP failure rates, strengthening or weakening EPSPs and enhancing or inhibiting short-term potentiation [STP synaptic augmentation (SA) and post-tetanic potentiation (PTP)], respectively. High Aß 40 concentrations induced inhibition regardless of synaptic type. D-connections were inhibited regardless of Aß species or concentration. The inhibition induced with bath application was hard to recover by washout, but a complete recovery was obtained with brief local application and prompt washout. Our data suggests that Aß 40 acts on the prefrontal neuronal network by modulating facilitating and depressing synapses. At higher levels, both Aß 40 and Aß 42 inhibit synaptic activity and cause irreversible toxicity once diffusely accumulated in the synaptic environment.