LAUSR

Prefrontal cortex (PFC)-related functions, such as working memory (WM) and cognitive flexibility (CF), are among the first to be altered at early stages of Alzheimer's disease (AD). Likewise, transgenic AD models carrying different AD-related mutations, mostly linked to the overproduction of amyloid beta (Aβ) and other peptides, show premature behavioral and functional symptoms associated with PFC alterations. However, little is known about the effects of intracerebral or intra-PFC Aβ infusion on WM and CF, as well as on pyramidal cell excitability and plasticity. Thus, here we evaluated the effects of a single Aβ injection, directly into the PFC, or its intracerebroventricular (icv) application, on PFC-dependent behaviors and on the intrinsic and synaptic properties of layer V pyramidal neurons in PFC slices. We found that a single icv Aβ infusion reduced learning and performance of a delayed non-matching-to-sample WM task and prevented reversal learning in a matching-to-sample version of the task, several weeks after its infusion. The inhibition of WM performance was reproduced more potently by a single PFC Aβ infusion and was associated with Aβ accumulation. This behavioral disruption was related to increased layer V pyramidal cell firing, larger sag membrane potential, increased fast after-hyperpolarization and a failure to sustain synaptic long-term potentiation, even leading to long-term depression, at both the hippocampal-PFC pathway and intracortical synapses. These findings show that Aβ can affect PFC excitability and synaptic plasticity balance, damaging PFC-dependent functions, which could constitute the foundations of the early alterations in executive functions in AD patients.